6-11 bicycle ketolide derivatives

ABSTRACT

The present invention discloses compounds of formula I, or pharmaceutically acceptable salts, esters, or prodrugs thereof: 
                         
which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.

This application is a continuation-in-part of application Ser. No.10/429,485 (filed May 5, 2003), now U.S. Pat. No. 6,878,691, which is acontinuation-in-part of application Ser. No. 10/144,558 (filed May 13,2002), now abandoned.

TECHNICAL FIELD

The present invention relates to novel semisynthetic macrolides havingantibacterial activity and useful in the treatment and prevention ofbacterial infections. More particularly, the invention relates to 6–11bicyclic ketolide derivatives, compositions containing such compoundsand methods for using the same, as well as processes for making suchcompounds.

BACKGROUND OF THE INVENTION

Macrolide antibiotics play a therapeutically important role,particularly with the emergence of new pathogens. Structural differencesare related to the size of the lactone ring and to the number and nature(neutral or basic) of the sugars. Macrolides are classified according tothe size of the lactone ring (12, 14, 15 or 16 atoms). The macrolideantibiotic family (14-, 15- and 16-membered ring derivatives) shows awide range of characteristics (antibacterial spectrum, side-effects andbioavailability). Among the commonly used macrolides are erythromycin,clarithromycin, and azithromycin. Macrolides possessing a 3-oxo moietyin place of the 3-cladinose sugar are known as ketolides and have shownenhanced activity towards gram-negative bacteria and macrolide resistantgram-positive bacteria. The search for macrolide compounds which areactive against MLS_(B)-resistant strains(MLS_(B)=Macrolides-Lincosamides-type B Streptogramines) has become amajor goal, together with retaining the overall profile of themacrolides in terms of stability, tolerance and pharmacokinetics.

SUMMARY OF THE INVENTION

The present invention provides a novel class of C6–C11 bridgederythromycin derivatives which possess antibacterial activity.

In one aspect of the present invention there are provided novel bridgedketolide compounds represented by formula I as illustrated below:

-   -   or a racemate, enantiomer, regioisomer, salt, ester or prodrug        thereof, wherein    -   A and B are independently selected from the group consisting of        hydrogen, deuterium, halogen, R₁, OR₁, S(O)_(n)R₁, —NR₁C(O)R₁,        —NR₁C(O)NR₃R₄, —NHS(O)_(n)R₁, —CONR₃R₄, and NR₃R₄;    -   Each R₁ is independently selected from the group consisting of        hydrogen, acyl, silane, a substituted or unsubstituted,        saturated or unsaturated aliphatic group, a substituted or        unsubstituted, saturated or unsaturated alicyclic group, a        substituted or unsubstituted aromatic group, a substituted or        unsubstituted heteroaromatic group, saturated or unsaturated        heterocyclic group;    -   R₃ and R₄ is independently selected from the group consisting of        hydrogen, acyl, a substituted or unsubstituted, saturated or        unsaturated aliphatic group, a substituted or unsubstituted,        saturated or unsaturated alicyclic group, a substituted or        unsubstituted aromatic group, a substituted or unsubstituted        heteroaromatic group, saturated or unsaturated heterocyclic        group; or can be taken together with the nitrogen atom to which        they are attached to form a substituted or unsubstituted        heterocyclic or heteroaromatic ring;    -   or A and B, taken together with the carbon atom to which they        are attached, form a substituted or unsubstituted alicyclic,        aromatic, heterocyclic or heteroaromatic ring;    -   or A and B, taken together with the carbon atom to which they        are attached, are selected from the group consisting of CO,        C═CHR₁, C═NR₁, C═NOR₁, C═NO(CH₂)_(m)R₁, C═NNHR₁, C═NNHCOR₁,        C═NNHCONR₁R₂, C═NNHS(O)_(n)R₁, or C═N—N═CHR₁;    -   X and Y are independently selected from the group consisting of        hydrogen, deuterium, halogen, R₁, OR₁, S(O)_(n)R₁, —NR₁C(O)R₁,        —NR₁C(O)NR₃R₄, —NR₁S(O)_(n)R₁, —CONR₃R₄, and NR₃R₄;    -   or X and Y, taken together with the carbon atom to which they        are attached, are selected from the group consisting of CO,        C═CHR₁, C═NR₁, C═NOR₁, C═NO(CH₂)_(m)R₁, C═NNHR₁, C═NNHCOR₁,        C═NNHCONR₁R₂, C═NNHS(O)_(n)R₁, or C═N—N═CHR₁;    -   L is selected from the group consisting of hydrogen, a        substituted or unsubstituted, saturated or unsaturated aliphatic        group, a substituted or unsubstituted, saturated or unsaturated        alicyclic group, a substituted or unsubstituted aromatic group,        a substituted or unsubstituted heteroaromatic group, saturated        or unsaturated heterocyclic group;    -   W is NR₃R₄    -   Z is hydrogen, alkyl or halogen;    -   R₂′ is R₁;    -   m is an integer; and    -   n is 0, 1, or 2.

Or a compound represented by formula I, or a racemate, enantiomer,regioisomer, salt, ester or prodrug thereof, wherein

-   A is selected from:    -   a) —OH;    -   b) —OR_(p), where R_(p) is a hydroxy protecting group;    -   c) —R₁, where R₁ is independently selected from:        -   (1) aryl;        -   (2) substituted aryl;        -   (3) heteroaryl;        -   (4) substituted heteroaryl;        -   (5) heterocycloalkyl; or        -   (6) substituted heterocycloalkyl;    -   d) —OR₁, where R₁ is as previously defined;    -   e) —R₂, where R₂ is selected from:        -   (1) hydrogen;        -   (2) halogen;        -   (3) C₁–C₁₂ alkyl optionally containing 0, 1, 2, or 3            heteroatoms selected from O, S(O)_(n), where n is 0, 1, or            2, or N, optionally substituted with one or more            substituents selected from halogen, aryl, substituted aryl,            heteroaryl, substituted heteroaryl, heterocycloalkyl, or            substituted heterocycloalkyl;        -   (4) C₂–C₁₂ alkenyl optionally containing 0, 1, 2, or 3            heteroatoms selected from O, S(O)_(n), where n is as            previously defined, and N, optionally substituted with one            or more substituents selected from halogen, aryl,            substituted aryl, heteroaryl, substituted heteroaryl,            heterocycloalkyl, or substituted heterocycloalkyl; and        -   (5) C₂–C₁₂ alkynyl optionally containing 0, 1, 2, or 3            heteroatoms selected from O, S(O)_(n), where n is as            previously defined, and N, optionally substituted with one            or more substituents selected from halogen, aryl,            substituted aryl, heteroaryl, substituted heteroaryl,            heterocycloalkyl, or substituted heterocycloalkyl;    -   f) —OR₂, where R₂ is independently previously defined;    -   g) —S(O)_(n)R₁₁, where n is as previously defined and R₁₁ is        independently hydrogen, R₁ or R₂, where R₁ and R₂ are as        previously defined;    -   h) —NHC(O)R₁₁, where R₁₁ is as previously defined;    -   i) —NHC(O)NHR₁₁, where R₁₁ is as previously defined;    -   j) —NHS(O)R₁₁, where n and R₁₁ are as previously defined;    -   k) —NR₁₄R₁₅, where R₁₄ and R₁₅ are each independently R₁₁, where        R₁₁ is as previously defined; or    -   l) —NHR₃, where R₃ is an amino protecting group;-   B is selected from:    -   a) hydrogen;    -   b) deuterium;    -   c) halogen;    -   d) —OH;    -   e) R₁, where R₁ is as previously defined;    -   f) R₂, where R₂ is as previously defined; or    -   g) —OR_(p), where R_(p) is as previously defined,    -   h) provided that when B is halogen, —OH, or —OR_(p), A is R₁ or        R₂;-   or alternatively, A and B taken together with the carbon atom to    which they are attached are selected from:    -   a) C(OR₁₆)(OR₁₇), where R₁₆ and R₁₇ taken together are        —(CH₂)_(m)—, and where m is 2 or 3;    -   b) C(SR₁₆)(SR₁₇), where R₁₆ and R₁₇ taken together are        —(CH₂)_(m) and, where m is as previously defined,    -   c) C═CHR₁₁, where R₁₁ is as previously defined;    -   d) C═N—O—Ar₁—M—Ar₂, wherein        -   (1) —Ar₁— is absent or selected from R₃₁, where R₃₁ is            independently selected from:            -   (a) R₁, where R₁ is as previously defined;            -   (b) C₁–C₁₂ alkyl optionally containing 0, 1, 2, or 3                heteroatoms selected from O, S(O)_(n), where n is as                previously defined, and N, optionally substituted with                one or more substituents selected from halogen, aryl,                substituted aryl, heteroaryl, substituted heteroaryl,                heterocycloalkyl, or substituted heterocycloalkyl;            -   (c) C₂–C₁₂ alkenyl optionally containing 0, 1, 2, or 3                heteroatoms selected from O, S(O)_(n), where n is as                previously defined, and N, optionally substituted with                one or more substituents selected from halogen, aryl,                substituted aryl, heteroaryl, substituted heteroaryl,                heterocycloalkyl, or substituted heterocycloalkyl; or            -   (d) C₂–C₁₂ alkynyl optionally containing 0, 1, 2, or 3                heteroatoms selected from O, S(O)_(n), where n is as                previously defined, and N, optionally substituted with                one or more substituents selected from halogen, aryl,                substituted aryl, heteroaryl, substituted heteroaryl,                heterocycloalkyl, or substituted heterocycloalkyl;        -   (2) —M— is absent or selected from:            -   (a) —C₁–C₁₂ alkyl optionally containing:                -   (1) 0–3 heteroatoms selected from O, S(O)_(n), where                    n is as previously defined, or N; and                -   (2) 0–3 groups selected from —C═N—, —N═N, —C(O)—;            -   (b) —C₂–C₁₂ alkenyl optionally containing:                -   (1) 0–3 heteroatoms selected from O, S(O)_(n), where                    n is as previously defined, or N; and                -   (2) 0–3 groups selected from —C═N—, —N═N, —C(O)—;            -   (c) —C₂–C₁₂ alkynyl optionally containing;                -   (1) 0–3 heteroatoms selected from O, S(O)_(n), where                    n is as previously defined, or N; and                -   (2) 0–3 groups selected from —C═N—, —N═N, —C(O)—;            -   (d) substituted aryl;            -   (e) substituted heteroaryl;            -   (f) heterocycloalkyl; or            -   (g) substituted heterocycloalkyl; and        -   (3) —Ar₂ is absent or selected from:            -   (a) aryl;            -   (b) substituted aryl;            -   (c) heteroaryl;            -   (d) substituted heteroaryl;            -   (e) heterocycloalkyl; or            -   (f) substituted heterocycloalkyl;    -   e) C═NNHR₁₁, where R₁₁ is as previously defined;    -   f) C═NNHC(O)R₁₁, where R₁₁ is as previously defined;    -   g) C═NNHC(O)NHR₁₁, where R₁₁ is as previously defined;    -   h) C═NNHS(O)_(n)R₁₁, where n and R₁₁ are as previously defined;    -   i) C═NNHR₃, where R₃ is as previously defined;    -   j) C═NR₁₁, where R₁₁ is as previously defined; or    -   k) C═N—N═CHR₁₁, where R₁₁ is as previously defined;-   one of X and Y is hydrogen and the other is selected from:    -   a) hydrogen;    -   b) deuterium;    -   c) —OH;    -   d) —OR_(p), where R_(p) is as previously defined;    -   e) —NR₄R₅, where R₄ and R₅ are each independently selected from:        -   (1) hydrogen;        -   (2) C₁–C₁₂ alkyl, optionally substituted with one or more            substituents selected from halogen, aryl, substituted aryl,            heteroaryl, substituted heteroaryl, heterocycloalkyl, or            substituted heterocycloalkyl; or        -   (3) R₄ and R₅, taken together with the nitrogen atom to            which they are attached to form a heterocycloalkyl moiety;-   alternatively, X and Y taken together with the carbon atom to which    they are attached are selected from:    -   a) C═O;    -   b) C═N—Q, wherein Q is selected from:        -   (1) —R₁₁, where R₁₁ is as previously defined;        -   (2) amino protecting group;        -   (3) —C(O)R₁₁, where R₁₁ is as previously defined;        -   (4) —OR₆, where R₆ is independently selected from:            -   a. hydrogen;            -   b. —CH₂O(CH₂)₂OCH₃,            -   c. —CH₂O(CH₂O)_(n)CH₃ where n is as previously defined;            -   d. —C₁–C₁₂ alkyl, optionally substituted with one or                more substituents selected from aryl, substituted aryl,                heteroaryl, substituted heteroaryl, heterocycloalkyl, or                substituted heterocycloalkyl;            -   e. —C₃–C₁₂ cycloalkyl;            -   f. —C(O)—C₁–C₁₂ alkyl;            -   g. —C(O)—C₃–C₁₂ cycloalkyl;            -   h. —C(O)—R₁, where R₁ is as previously defined; or            -   i. —Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and                R_(c) are each independently selected from C₁–C₁₂ alkyl,                aryl or substituted aryl; or        -   (5) O—C(R₇)(R₈)—O—R₆, where R₆ is as previously defined,            provided that R₆ is not C(O)—C₁–C₁₂ alkyl, C(O)—C₃–C₁₂            cycloalkyl, or C(O)—R₁, and R₇ and R₈ taken together with            the carbon atom to which they are attached form a C₃–C₁₂            cycloalkyl group or each independently is selected from:            -   a. hydrogen; or            -   b. C₁–C₁₂ alkyl;-   L is selected from:    -   a) —CH₃;    -   b) —CH₂CH₃;    -   c) —CH(OH)CH₃;    -   d) —(CH₂)_(n)NHC(O)—R₁₁, wherein n and R₁₁ are as previously        defined;    -   e) C₁–C₆ alkyl, optionally substituted with one or more        substituents selected from aryl, substituted aryl, heteroaryl,        substituted heteroaryl, heterocycloalkyl, or substituted        heterocycloalkyl;    -   f) C₂–C₆ alkenyl, optionally substituted with one or more        substituents selected from aryl, substituted aryl, heteroaryl,        substituted heteroaryl, heterocycloalkyl, or substituted        heterocycloalkyl; or    -   g) C₂–C₆ alkynyl, optionally substituted with one or more        substituents selected from aryl, substituted aryl, heteroaryl,        substituted heteroaryl, heterocycloalkyl, or substituted        heterocycloalkyl;-   W is —NR₂₀R₂₁, where R₂₀ and R₂₁ are each independently selected    from:    -   a) hydrogen;    -   b) C₁–C₁₂ alkyl, optionally substituted with one or more        substituents selected from halogen, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, heterocycloalkyl, or        substituted heterocycloalkyl;    -   c) C₂–C₁₂ alkenyl, optionally substituted with one or more        substituents selected from halogen, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, heterocycloalkyl, or        substituted heterocycloalkyl;    -   d) C₂–C₁₂ alkynyl, optionally substituted with one or more        substituents selected from halogen, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, heterocycloalkyl, or        substituted heterocycloalkyl; or    -   e) R₂₀ and R₂₁, taken together with the nitrogen atom to which        they are attached form a heterocycloalkyl moiety; or-   Z is selected from:    -   a) hydrogen;    -   b) methyl; or    -   c) halogen; and-   R₂′ is hydrogen, or R_(p), where R_(p), is as previously defined.

In another embodiment of the present invention there are disclosedpharmaceutical compositions comprising a therapeutically effectiveamount of any compound of the present invention in combination with apharmaceutically acceptable carrier or excipient. In yet anotherembodiment of the invention are methods of treating antibacterialinfections in a subject with said pharmaceutical compositions. Suitablecarriers and methods of formulation are also disclosed.

In a further aspect of the present invention there are providedprocesses for the preparation of 6,11-3C-bridged ketolide derivatives offormula (I) via any synthetic route delineated herein.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the present invention is a compound of formula Ias defined herein, or its pharmaceutically acceptable salt, ester, orprodrug.

Representative subgenera of the present invention are:

-   -   A compound according to claim 1 which is represented by the        formula

-   -    wherein A, B, R₂′, Q, W, and Z are as defined in claim;    -   A compound according to claim 1 which is represented by the        formula

-   -    wherein A, B, R₂′, Q, and Z are as defined in claim 1;    -   A compound according to claim 1 which is represented by the        formula

-   -    wherein A, B, R₂′, Q, and Z are as defined in claim 1;    -   A compound according to claim 1 which is represented by the        formula

-   -    wherein Ar₁, Ar₂, R₂′, M, Q, W, and Z are as defined in claim        1;    -   A compound according to claim 1 which is represented by the        formula:

-   -    wherein Ar₁, Ar₂, R₂′, M, Q, and Z are as defined in claim 1;    -   A compound according to claim 1 which is represented by the        formula:

-   -    wherein Ar₁, Ar₂, R₂′, M, and Z are as defined in claim 1; or    -   A compound according to claim 1 which is represented by the        formula:

-   -    wherein Ar₁, Ar₂, R₂′, M, and Q are as defined in claim 1.

-   Compound of formula I, wherein B is hydrogen or OH;

-   Compound of formula I, wherein A and B taken together with the    carbon atom to which they are attached are C═CH—R₁₁;

-   Compound of formula I, wherein A and B taken together with the    carbon atom to which they are attached are C═CH—R₁₁ and X and Y    taken together with the carbon atom to which they are attached are    C═N—Q;

-   Compound of formula I, wherein A and B taken together with the    carbon atom to which they are attached are C═CH—R₁₁ and X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac;

-   Compound of formula I, wherein X and Y taken together with the    carbon atom to which they are attached are C═N—Q; or

-   Compound of formula I, wherein A and B taken together with the    carbon atom to which they are attached are selected from:    -   (a) C═N—NHR₁₁, where R₁₁ is as defined in claim 1;    -   (b) C═N—NHC(O)R₁₁, where R₁₁ is as previously defined;    -   (c) C═N—NHC(O)NHR₁₁, where R₁₁ is as previously defined;    -   (d) C═N—NHS(O)₂R₁₁, where R₁₁ is as previously defined;    -   (e) C═N—NHR₃, where R₃ is as defined in claim 1;    -   (f) C═N—R₁₁, where R₁₁ is as previously defined; or    -   (g) C═N—N═CHR₁₁, where R₁₁ is as previously defined.        Representative species of the present invention are:

-   Example 1. Compound of formula I: A and B taken together with the    carbon atom to which they attached are C═CH₂, X and Y taken together    with the carbon atom to which they are attached are C═N—Ac,    L═CH₂CH₃, Z═H, and R₂′═Ac;

-   Example 2. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH₂, X and Y taken    together with the carbon atom to which they are attached are C═N—Ac,    L═CH₂CH₃, Z═H and R₂′═H;

-   Example 3. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═O, X and Y taken    together with the carbon atom to which they attached are C═N—Ac,    L═CH₂CH₃, Z═H and R₂′═H;

-   Example 4. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═N—O—CH₂-Ph, X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H and R₂′═H;

-   Example 5. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═N—O—CH₂—(3-pyridyl), X    and Y taken together with the carbon atom to which they are attached    are C═N—Ac, L═CH₂CH₃, Z═H and R₂′═H;

-   Example 6. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═N—O—CH₂—(2-pyridyl), X    and Y taken together with the carbon atom to which they are attached    are C═N—Ac, L═CH₂CH₃, Z═H and R₂′═H;

-   Example 7. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═N—O—CH₂—(3-quinolyl), X    and Y taken together with the carbon atom to which they are attached    are C═N—Ac, L═CH₂CH₃, Z═H and R₂′═H;

-   Example 8. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═N—O—CH₂—(2-quinolyl), X    and Y taken together with the carbon atom to which they are attached    are C═N—Ac, L═CH₂CH₃, Z═H and R₂′═H;

-   Example 9. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are    C═N—O—CH₂(5-pyridin-2-ylthiophen-2yl), X and Y taken together with    the carbon atom to which they are attached are C═N—Ac, L═CH₂CH₃, Z═H    and R₂′═H;

-   Example 10. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are    C═N—O—[3-(pyrimidin-2-yl)prop-2-ynyl], X and Y taken together with    the carbon atom to which they are attached are C═N—Ac, L═CH₂CH₃, Z═H    and R₂′═H;

-   Example 11. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═N—O-Ph, X and Y taken    together with the carbon atom to which they are attached are C═N—Ac,    L═CH₂CH₃, Z═H and R₂′═H;

-   Example 12. Compound of formula I: A═NHCH₂-Ph, B═H, X and Y taken    together with the carbon atom to which they are attached are C═N—Ac,    L═CH₂CH₃, Z═H and R₂′═H;

-   Example 13. Compound of formula I: A═NHCH₂CH₂-Ph, B═H, X and Y taken    together with the carbon atom to which they are attached are C═N—Ac,    L═CH₂CH₃, Z═H and R₂′═H;

-   Example 14. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH₂, X and Y taken    together with the carbon atom to which they are attached are    C═N—O—CH₂—O—CH₃, L═CH₂CH₃, Z═H, and R₂′═Ac;

-   Example 15. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH₂, X and Y taken    together with the carbon atom to which they are attached are    C═N—O—CH₂—O—CH₃, L═CH₂CH₃, Z═H and R₂′═H;

-   Example 16. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═O, X and Y taken    together with the carbon atom to which they are attached are    C═N—O—CH₂—O—CH₃, L═CH₂CH₃, Z═H and R₂′═H;

-   Example 17. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═NOCH₂-Ph, X and Y taken    together with the carbon atom to which they are attached are    C═N—O—CH₂—O—CH₃, L═CH₂CH₃, Z═H and R₂′═H;

-   Example 18. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═O, X and Y taken    together with the carbon atom to which they are attached are C═O,    L═CH₂CH₃, Z═H, and R₂′═Ac;

-   Example 19. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH₂, X and Y taken    together with the carbon atom to which they are attached are C═O,    L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 20. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═O, X and Y taken    together with the carbon atom to which they are attached are C═O,    L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 21. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═N—O—CH₂-Ph, X and Y    taken together with the carbon atom to which they are attached are    C═O, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 22. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH₂, X and Y taken    together with the carbon atom to which they are attached are C═NH,    L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 23. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═N—O—CH₂-p-NO₂-Ph, X and    Y taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 24. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═N—O—(CH₂)₂-Ph, X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 25. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═N—O—(CH₂)₃-Ph, X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 26. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═N—O—CH₂—CH═CH-Ph, X and    Y taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 27. Compound of formula I: A is NH—(CH₂)₃-Ph, B is H, X and    Y taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 28. Compound of formula I: A is NH—(CH₂)₄-Ph, B is H, X and    Y taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 29. Compound of formula I: A is CH₂—CH═CH₂, B is OH, X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 30. Compound of formula I: A is CH₂-Ph, B is OH, X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 31. Compound of formula I: A is Ph, B is OH, X and Y taken    together with the carbon atom to which they are attached are C═N—Ac,    L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 32. Compound of formula I: A is Ph, B is OH, X and Y taken    together with the carbon atom to which they are attached are C═N—Ac,    L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 33. Compound of formula I: A is CH₂—CH═CH-Ph, B is OH, X and    Y taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 34. Compound of formula I: A is (CH₂)₃-Ph, B is OH, X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 35. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH—CH═CH-Ph, X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 36. Compound of formula I: A is (CH₂)₃-Ph, B is H, X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 37. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH—CH═CH-3-pyridyl, X    and Y taken together with the carbon atom to which they are attached    are C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 38. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH—CH═CH-3-quinolyl, X    and Y taken together with the carbon atom to which they are attached    are C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 39. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH-2-quinolyl, X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 40. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH-2-quinolyl, X and Y    taken together with the carbon atom to which they are attached are    C═N—H, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 41. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH-4-biphenyl, X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 42. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH-3-biphenyl, X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 43. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH-4-phenoxyphenyl, X    and Y taken together with the carbon atom to which they are attached    are C═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 44. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═CH-Ph, X and Y taken    together with the carbon atom to which they are attached are C═N—Ac,    L═CH₂CH₃, Z═H, and R₂′═H;

-   Example 45. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are    C═CH-2-(2pyridyl)-thiophen-5-yl, X and Y taken together with the    carbon atom to which they are attached are C═N—Ac, L═CH₂CH₃, Z═H,    and R₂′═H; or

-   Example 46. Compound of formula I: A and B taken together with the    carbon atom to which they are attached are C═O, X and Y taken    together with the carbon atom to which they are attached are C═N—Ac,    L═CH₂CH₃, Z═F, and R₂′═Ac.

Further representative species of the present invention are:

Example compounds 47–114 of the formula A:

-   -   wherein Ar₁, Ar₂, M, Q, and Z are delineated for each example in        Table A:

TABLE A Example Q —Ar₁—M—Ar₂ Z Example 47. Ac

H Example 48. Ac

H Example 49. Ac

H Example 50. Ac

H Example 51. Ac

H Example 52. Ac

H Example 53. Ac

H Example 54. Ac

H Example 55. MOM

H Example 56. Ac

H Example 57. Ac

H Example 58. Ac

H Example 59. Ac

H Example 60. Ac

H Example 61. Ac

H Example 62. Ac

H Example 63. Ac

H Example 64. Ac

H Example 65. Ac

H Example 66. Ac

H Example 67. Ac

H Example 68. Ac

H Example 69. Ac

H Example 70. Ac

H Example 71. Ac

H Example 72. Ac

H Example 73. Ac

H Example 74. Ac

H Example 75. Ac

H Example 76. Ac

H Example 77. Ac

H Example 78. Ac

H Example 79. Ac

H Example 80. Ac

F Example 81. H

H Example 82. Ac

H Example 83. Ac

F Example 84. Ac

H Example 85. Ac

H Example 86. Ac

H Example 87. Ac

H Example 88. Ac

H Example 89. Ac

H Example 90. H

H Example 91. H

H Example 92. OMe

H Example 93. —OMOM

H Example 94. —OCH₂CN

H Example 95. —OCH₂CH₂OH

H Example 96. H

H Example 97. Ac

H Example 98. Ac

H Example 99. Ac

H Example 100. Ac

H Example 101. Ac

H Example 102. Ac

H Example 103. Ac

H Example 104. Ac

H Example 105. Ac

H Example 106. Ac

H Example 107. Ac

H Example 108. Ac

H Example 109. Ac

H Example 110. Ac

H Example 111. Ac

H Example 112. Ac

H Example 113. Ac

H Example 114. Ac

H

Example compounds 115–263 of formula A1:

-   -   wherein Ar₁, Ar₂, M, Q, and Z are delineated for each example in        Table A1:

TABLE A1 Example Q —Ar₁—M—Ar₂ Z Example 115. Ac

H Example 116. Ac

H Example 117. Ac

H Example 118. Ac

H Example 119. Ac

H Example 120. Ac

H Example 121. Ac

H Example 122. Ac

H Example 123. Ac

H Example 124. Ac

H Example 125. Ac

H Example 126. Ac

H Example 127. Ac

H Example 128. Ac

H Example 129. Ac

H Example 130. Ac

H Example 131. Ac

H Example 132. Ac

H Example 133. Ac

H Example 134. Ac

H Example 135. Ac

H Example 136. Ac

H Example 137. Ac

H Example 138. Ac

F Example 139. Ac

H Example 140. Ac

F Example 141. Ac

F Example 142. Ac

F Example 143. Ac

H Example 144. Ac

H Example 145. Ac

H Example 146. Ac

H Example 147. Ac

H Example 148. Ac

F Example 149. Ac

H Example 150. Ac

F Example 151. Ac

H Example 152. Ac

H Example 153. Ac

H Example 154. Ac

H Example 155. Ac

H Example 156. Ac

H Example 157. Ac

H Example 158. Ac

H Example 159. Ac

H Example 160. Ac

H Example 161. Ac

H Example 162. Ac

H Example 163. Ac

H Example 164. Ac

H Example 165. Ac

H Example 166. Ac

H Example 167. Ac

H Example 168. Ac

H Example 169. Ac

H Example 170. Ac

H Example 171. Ac

H Example 172. Ac

H Example 173. Ac

F Example 174. Ac

F Example 175. Ac

H Example 176. Ac

H Example 177. Ac

H Example 178. Ac

H Example 179. Ac

H Example 180. H

H Example 181. Ac

H Example 182. Ac

H Example 183. Ac

H Example 184. Ac

F Example 185. Ac

H Example 186. Ac

H Example 187. Ac

H Example 188. Ac

H Example 189. Ac

F Example 190. Ac

H Example 191. H

H Example 192. Ac

H Example 193. Ac

H Example 194. H

H Example 195. Ac

H Example 196. H

H Example 197. H

H Example 198. H

H Example 199. Ac

H Example 200. Ac

H Example 201. Ac

H Example 202. H

H Example 203. H

H Example 204. H

H Example 205. Ac

H Example 206. H

H Example 207. Ac

H Example 208. Ac

H Example 209. Ac

H Example 210. Ac

H Example 211. Ac

F Example 212. H

F Example 213. H

H Example 214. Ac

F Example 215. Ac

H Example 216. Ac

F Example 217. Ac

H Example 218. Ac

H Example 219. Ac

H Example 220. Ac

F Example 221. Ac

H Example 222. Ac

H Example 223. Ac

H Example 224. Ac

H Example 225. Ac

H Example 226. Ac

H Example 227. Ac

H Example 228. Ac

H Example 229. Ac

H Example 230. H

F Example 231. H

H Example 232. Ac

H Example 233. Ac

H Example 234. Ac

H Example 235. Ac

H Example 236. Ac

H Example 237. Ac

H Example 238. Ac

H Example 239. Ac

H Example 240. Ac

H Example 241. Ac

H Example 242. Ac

H Example 243. Ac

H Example 244. Ac

H Example 245. Ac

H Example 246. Ac

H Example 247. Ac

H Example 248. Ac

H Example 249. Ac

H Example 250. Ac

H Example 251. Ac

H Example 252. Ac

H Example 253. Ac

H Example 254. Ac

H Example 255. Ac

H Example 256. Ac

H Example 257. H

H Example 258. Ac

H Example 259. Ac

H Example 260. Ac

H Example 261. —COCH₂CH₃

H Example 262. Ac

H Example 263. Ac

H

Example compounds 264–338 of formula A2:

-   -   wherein Ar₁, Ar₂, M, Q, and Z are delineated for each example in        Table A2:

TABLE A2 Example Q -Ar₁-M-Ar₂ Z Example 264. Ac

H Example 265. Ac

H Example 266. Ac

H Example 267. Ac

H Example 268. Ac

H Example 269. Ac

H Example 270. Ac

H Example 271. Ac

H Example 272. Ac

F Example 273. Ac

H Example 274. Ac

F Example 275. Ac

F Example 276. Ac

H Example 277. Ac

H Example 278. Ac

H Example 279. Ac

F Example 280. Ac

H Example 281. Ac

H Example 282. Ac

H Example 283. Ac

H Example 284. Ac

H Example 285. Ac

H Example 286. Ac

H Example 287. Ac

H Example 288. Ac

H Example 289. Ac

H Example 290. Ac

H Example 291. Ac

H Example 292. Ac

H Example 293. Ac

H Example 294. Ac

H Example 295. Ac

F Example 296. Ac

H Example 297. Ac

H Example 298. Ac

H Example 299. Ac

H Example 300. H

H Example 301. Ac

H Example 302. Ac

H Example 303. H

H Example 304. H

F Example 305. Ac

H Example 306. Ac

H Example 307. Ac

H Example 308. Ac

H Example 309. Ac

H Example 310. Ac

H Example 311. Ac

H Example 312. Ac

H Example 313. Ac

F Example 314. Ac

H Example 315. Ac

H Example 316. Ac

F Example 317. Ac

H Example 318. Ac

F Example 319. Ac

H Example 320. Ac

H Example 321. Ac

H Example 322. Ac

H Example 323. Ac

H Example 324. Ac

H Example 325. Ac

H Example 326. Ac

H Example 327. Ac

H Example 328. Ac

H Example 329. Ac

H Example 330. Ac

H Example 331. Ac

H Example 332. Ac

H Example 333. Ac

H Example 334. Ac

H Example 335. Ac

H Example 336. Ac

H Example 337. H

H Example 338. Ac

H

Example compounds 339–353 of formula B:

-   -   wherein R₁₁, Q, and Z are delineated for each example in Table        B:

TABLE B Example Q R₁₁ Z Example 339. H H H Example 340. OMOM H H Example341. OMOM

H Example 342. Ac

H Example 343. Ac

H Example 344. Ac

H Example 345. Ac

H Example 346. Propionyl

H Example 347. Ac

H Example 348. Methyl carbamate

H Example 349. urea H H Example 350. Me H H Example 351. BOM H H Example352. Ac

H Example 353. Ac

H

Example compounds 354–376 of formula B1:

-   -   wherein R₁₁, Q, and Z are delineated for each example in Table        B1:

Examples Q R₁₁ Z Example 354. Ac

H Example 355. Ac

H Example 356. Ac

H Example 357. Ac

H Example 358. Ac

H Example 359. Ac

H Example 360. Ac

F Example 361. Ac

H Example 362. Ac

H Example 363. Ac

H Example 364. 2-methoxyacetamide

H Example 365. 2-O-acyl-acetamide

H Example 366. 2-Fmoc-acetamide

H Example 367. Ac

H Example 368. Ac

H Example 369. 2-hydroxy acetyl

H Example 370. 2-aminoacetyl

H Example 371. Ac

H Example 372. Ac

H Example 373. Ac

H Example 374. Ac

H Example 375. Ac

H

Example compounds 376–384 of formula B2:

-   -   wherein R₁₁, Q, and Z are delineated for each example in Table        B2:

TABLE B2 Example Q R₁₁ Z Example 376. Ac

H Example 377. Ac

H Example 378. Ac

H Example 379. Ac

H Example 380. Ac

H Example 381. Ac

H Example 382. Ac

H Example 383. Ac

H Example 384. Ac

H

Example compounds 385–391 of formula C:

-   -   wherein R₁₁, Q, and Z are delineated for each example in Table        C:

TABLE C Example Q R₁₁ Z Example 385. Ac

H Example 386. Ac

H Example 387. Ac

H Example 388. Ac

H Example 389. Ac

H Example 390. Ac

H Example 391. Ac

H

A further embodiment of the present invention includes pharmaceuticalcompositions comprising any single compound delineated herein, or apharmaceutically acceptable salt, ester, or prodrug thereof, with apharmaceutically acceptable carrier or excipient.

Yet another embodiment of the present invention is a pharmaceuticalcomposition comprising a combination of two or more compounds delineatedherein, or a pharmaceutically acceptable salt, ester, or prodrugthereof, with a pharmaceutically acceptable carrier or excipient.

Yet a further embodiment of the present invention is a pharmaceuticalcomposition comprising any single compound delineated herein incombination with one or more antibiotics known in the art (such aspenicillin, amoxicillin, azithromycin, erythromycin, ciproflaxin,telithromycin, cethromycin, and the like) or a pharmaceuticallyacceptable salt, ester, or prodrug thereof, with a pharmaceuticallyacceptable carrier or excipient.

Yet an additional aspect of the present invention relates to a method oftreating a subject (e.g., mammal, human, horse, dog, cat, fish) havingbacterial infection or disease or disease symptom related to having abacterial infection (including diseases delineated herein). The methodincludes administering to the subject (including a subject identified asin need of such treatment) an effective amount of a compound describedherein, or a composition described herein to produce such effect.Identifying a subject in need of such treatment can be in the judgmentof a subject or a health care professional and can be subjective (e.g.opinion) or objective (e.g. measurable by a test or diagnostic method).

Also within the scope of this invention is a packaged product. Thepackaged product includes a container, one of the aforementionedcompounds in the container, and a legend (e.g., a label or an insert)associated with the container and indicating administration of thecompound for treating a disorder associated with bacterial infection,including the diseases delineated herein.

In addition, the present invention contemplates processes of making anycompound delineated herein via any synthetic method delineated herein.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

An “aliphatic group” is non-aromatic moiety that may contain anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contain one or more units ofunsaturation, e.g., double and/or triple bonds. An aliphatic group maybe straight chained, branched or cyclic and preferably contains betweenabout 1 and about 24 carbon atoms, more typically between about 1 andabout 12 carbon atoms. In addition to aliphatic hydrocarbon groups,aliphatic groups include, for example, polyalkoxyalkyls, such aspolyalkylene glycols, polyamines, and polyimines, for example. Suchaliphatic groups may be further substituted.

The terms “C₁–C₃ alkyl,” “C₁–C₆ alkyl,” or “C₁–C₁₂ alkyl,” as usedherein, refer to saturated, straight- or branched-chain hydrocarbonradicals containing between one and three, one and twelve, or one andsix carbon atoms, respectively. Examples of C₁–C₃ alkyl radicals includemethyl, ethyl, propyl and isopropyl radicals; examples of C₁–C₆ alkylradicals include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, neopentyl andn-hexyl radicals; and examples of C₁–C₁₂ alkyl radicals include, but arenot limited to, ethyl, propyl, isopropyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl radicals and the like.

The term “substituted alkyl,” as used herein, refers to an alkyl, suchas a C₁–C₁₂ alkyl or C₁–C₆ alkyl group, substituted by one, two, threeor more aliphatic substituents.

Suitable aliphatic substituents include, but are not limited to, —F,—Cl, —Br, —I, —OH, protected hydroxy, aliphatic ethers, aromatic ethers,oxo, —NO₂, —CN, —C₁–C₁₂-alkyl optionally substituted with halogen (suchas perhaloalkyls), C₂–C₁₂-alkenyl optionally substituted with halogen,—C₂–C₁₂-alkynyl optionally substituted with halogen, —NH₂, protectedamino, —NH—C₁–C₁₂-alkyl, —NH—C₂–C₁₂-alkenyl, —NH—C₂–C₁₂-alkenyl,—NH—C₃–C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁–C₁₂-alkyl,—O—C₂–C₁₂-alkenyl, —O—C₂–C₁₂-alkynyl, —O—C₃–C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁–C₁₂-alkyl,—C(O)—C₂–C₁₂-alkenyl, —C(O)—C₂–C₁₂-alkynyl, —C(O)—C₃–C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁–C₁₂-alkyl, —CONH—C₂–C₁₂-alkenyl, —CONH—C₂–C₁₂-alkynyl,—CONH—C₃–C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —CO₂—C₁–C₁₂-alkyl, —CO₂—C₂–C₁₂-alkenyl,—CO₂—C₂–C₁₂-alkynyl, —CO₂—C₃–C₁₂-cycloalkyl, —CO₂-aryl, —CO₂-heteroaryl,—CO₂-heterocycloalkyl, —OCO₂—C₁–C₁₂-alkyl, —OCO₂—C₂–C₁₂-alkenyl,—OCO₂—C₂–C₁₂-alkynyl, —OCO₂—C₃–C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁–C₁₂-alkyl,—OCONH—C₂–C₁₂-alkenyl, —OCONH—C₂–C₁₂-alkynyl, —OCONH—C₃–C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁–C₁₂-alkyl, —NHC(O)—C₂–C₁₂-alkenyl, —NHC(O)—C₂–C₁₂-alkynyl,—NHC(O)—C₃–C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁–C₁₂-alkyl, —NHCO₂—C₂–C₁₂-alkenyl,—NHCO₂—C₂–C₁₂-alkynyl, —NHCO₂—C₃–C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁–C₁₂-alkyl, —NHC(O)NH—C₂–C₁₂-alkenyl,—NHC(O)NH—C₂–C₁₂-alkynyl, —NHC(O)NH—C₃–C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁–C₁₂-alkyl, —NHC(S)NH—C₂–C₁₂-alkenyl,—NHC(S)NH—C₂–C₁₂-alkynyl, —NHC(S)NH—C₃–C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁–C₂-alkyl, —NHC(NH)NH—C₂–C₁₂-alkenyl,—NHC(NH)NH—C₂–C₁₂-alkynyl, —NHC(NH)NH—C₃–C₂-cycloalkyl, —NHC(NH)NH-aryl,—NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl, NHC(NH)—C₁–C₁₂-aryl,—NHC(NH)—C₂–C₁₂-alkenyl, —NHC(NH)—C₂–C₁₂-alkynyl,—NHC(NH)—C₃–C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁–C₁₂-alkyl,—C(NH)NH—C₂–C₁₂-alkenyl, —C(NH)NH—C₂–C₁₂-alkynyl,—C(NH)NH—C₃–C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)-C₁–C₁₂-alkyl, —S(O)—C₂–C₁₂-alkenyl,—S(O)—C₂–C₁₂-alkynyl, —S(O)—C₃–C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁–C₁₂-alkyl,—SO₂NH—C₂–C₁₂-alkenyl, —SO₂NH—C₂–C₁₂-alkynyl, —SO₂NH—C₃–C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁–C₁₂-alkyl, —NHSO₂—C₂–C₁₂-alkenyl, —NHSO₂—C₂–C₁₂-alkynyl,—NHSO₂—C₃–C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃–C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁–C₁₂-alkyl, —S—C₂–C₁₂-alkenyl, —S—C₂–C₁₂-alkynyl,—S—C₃–C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkylsand the like can be further substituted.

The terms “C₂–C₁₂ alkenyl” or “C₂–C₆ alkenyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbondouble bond by the removal of a single hydrogen atom. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, alkadienes and the like.

The term “substituted alkenyl,” as used herein, refers to a “C₂–C₁₂alkenyl” or “C₂–C₆ alkenyl” group as previously defined, substituted byone, two, three or more aliphatic substituents.

The terms “C₂–C₁₂ alkynyl” or “C₂–C₆ alkynyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbontriple bond by the removal of a single hydrogen atom. Representativealkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, and the like.

The term “substituted alkynyl,” as used herein, refers to a “C₂–C₁₂alkynyl” or “C₂–C₆ alkynyl” group as previously defined, substituted byone, two, three or more aliphatic substituents.

The term “C₁–C₆ alkoxy,” as used herein, refers to a C₁–C₆ alkyl group,as previously defined, attached to the parent molecular moiety throughan oxygen atom. Examples of C₁–C₆-alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The term “aryl,” as used herein, refers to a mono- or bicycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyland the like.

The term “substituted aryl,” as used herein, refers to an aryl group, aspreviously defined, substituted by one, two, three or more aromaticsubstituents.

Aromatic substituents include, but are not limited to, —F, —Cl, —Br, —I,—OH, protected hydroxy, aliphatic ethers, aromatic ethers, oxo, —NO₂,—CN, —C₁–C₁₂-alkyl optionally substituted with halogen (such asperhaloalkyls), C₂–C₁₂-alkenyl optionally substituted with halogen,—C₂–C₁₂-alkynyl optionally substituted with halogen, —NH₂, protectedamino, —NH—C₁–C₁₂-alkyl, —NH—C₂–C₁₂-alkenyl, —NH—C₂–C₁₂-alkenyl,—NH—C₃–C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁–C₁₂-alkyl,—O—C₂–C₂-alkenyl, —O—C₂–C₂-alkynyl, —O—C₃–C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁–C₁₂-alkyl,—C(O)—C₂–C₁₂-alkenyl, —C(O)—C₂–C₁₂-alkynyl, —C(O)—C₃–C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁–C₁₂-alkyl, —CONH—C₂–C₁₂-alkenyl, —CONH—C₂–C₂-alkynyl,—CONH—C₃–C₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —CO₂—C₁–C₁₂-alkyl, —CO₂—C₂–C₁₂-alkenyl,—CO₂—C₂–C₁₂-alkynyl, —CO₂—C₃–C₁₂-cycloalkyl, —CO₂-aryl, —CO₂-heteroaryl,—CO₂-heterocycloalkyl, —OCO₂—C₁–C₁₂-alkyl, —OCO₂—C₂–C₁₂-alkenyl,—OCO₂—C₂-C₂-alkynyl, —OCO₂—C₃–C₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁–C₁₂-alkyl,—OCONH—C₂–C₁₂-alkenyl, —OCONH—C₂–C₁₂-alkynyl, —OCONH—C₃–C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁–C₁₂-alkyl, —NHC(O)—C₂–C₁₂-alkenyl, —NHC(O)—C₂–C₁₂-alkynyl,—NHC(O)—C₃–C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁–C₁₂-alkyl, —NHCO₂—C₂–C₁₂-alkenyl,—NHCO₂—C₂–C₁₂-alkynyl, —NHCO₂—C₃–C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁–C₁₂-alkyl, —NHC(O)NH—C₂–C₁₂-alkenyl,—NHC(O)NH—C₂–C₁₂-alkynyl, —NHC(O)NH—C₃–C₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁–C₂-alkyl, —NHC(S)NH—C₂–C₁₂-alkenyl,—NHC(S)NH—C₂–C₁₂-alkynyl, —NHC(S)NH—C₃–C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁–C₁₂-alkyl, —NHC(NH)NH—C₂–C₁₂alkenyl,—NHC(NH)NH—C₂–C₁₂-alkynyl, —NHC(NH)NH—C₃–C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)-C₁–C₁₂-alkyl, —NHC(NH)—C₂–C₁₂-alkenyl, —NHC(NH)—C₂–C₁₂-alkynyl,—NHC(NH)—C₃–C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH-C₁–C₁₂-alkyl,—C(NH)NH—C₂–C₁₂-alkenyl, —C(NH)NH—C₂–C₁₂-alkynyl,—C(NH)NH—C₃–C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁–C₁₂-alkyl, —S(O)—C₂–C₁₂-alkenyl,—S(O)—C₂–C₁₂-alkynyl, —S(O)—C₃–C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH-C₁–C₁₂-alkyl,—SO₂NH—C₂–C₁₂-alkenyl, —SO₂NH—C₂–C₂-alkynyl, —SO₂NH—C₃–C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁–C₁₂-alkyl, —NHSO₂—C₂–C₁₂-alkenyl, —NHSO₂—C₂–C₁₂-alkynyl,—NHSO₂—C₃–C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃–C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁–C₁₂-alkyl, —S—C₂–C₁₂-alkenyl, —S—C₂–C₁₂-alkynyl,—S—C₃–C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkylsand the like can be further substituted.

The term “arylalkyl,” as used herein, refers to an aryl group attachedto the parent compound via a C₁–C₃ alkyl or C₁–C₆ alkyl residue.Examples include, but are not limited to, benzyl, phenethyl and thelike.

The term “substituted arylalkyl,” as used herein, refers to an arylalkylgroup, as previously defined, substituted by one, two, three or morearomatic substituents.

The term “heteroaryl,” as used herein, refers to a mono-, bi-, ortri-cyclic aromatic radical or ring having from five to ten ring atomsof which at least one ring atom is selected from S, O and N; zero, oneor two ring atoms are additional heteroatoms independently selected fromS, O and N; and the remaining ring atoms are carbon, wherein any N or Scontained within the ring may be optionally oxidized. Heteroarylincludes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike. The heteroaromatic ring may be bonded to the chemical structurethrough a carbon or hetero atom.

The term “substituted heteroaryl,” as used herein, refers to aheteroaryl group as previously defined, substituted by one, two, threeor four aromatic substituents.

The term “C₃–C₁₂-cycloalkyl,” as used herein, denotes a monovalent groupderived from a monocyclic or bicyclic saturated carbocyclic ringcompound by the removal of a single hydrogen atom. Examples include, butnot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, and bicyclo[2.2.2] octyl.

The term “substituted C₃–C₁₂-cycloalkyl,” as used herein, refers to aC₃–C₁₂-cycloalkyl group as previously defined, substituted by one, two,three or more aliphatic substituents.

The term “heterocycloalkyl,” as used herein, refers to a non-aromatic5-, 6- or 7-membered ring or a bi- or tri-cyclic group fused system,where (i) each ring contains between one and three heteroatomsindependently selected from oxygen, sulfur and nitrogen, (ii) each5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms mayoptionally be oxidized, (iv) the nitrogen heteroatom may optionally bequaternized, (iv) any of the above rings may be fused to a benzene ring,and (v) the remaining ring atoms are carbon atoms which may beoptionally oxo-substituted. Representative heterocycloalkyl groupsinclude, but are not limited to, [1,3]dioxolane, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl.

The term “substituted heterocycloalkyl,” as used herein, refers to aheterocycloalkyl group, as previously defined, substituted by one, two,three or more aliphatic substituents.

The term “heteroarylalkyl,” as used herein, to an heteroaryl groupattached to the parent compound via a C₁–C₃ alkyl or C₁–C₆ alkylresidue. Examples include, but are not limited to, pyridinylmethyl,pyrimidinylethyl and the like.

The term “substituted heteroarylalkyl,” as used herein, refers to aheteroarylalkyl group, as previously defined, substituted by independentreplacement of one, two, or three or more aromatic substituents.

The term “C₁–C₃-alkylamino,” as used herein, refers to one or twoC₁–C₃-alkyl groups, as previously defined, attached to the parentmolecular moiety through a nitrogen atom. Examples of C₁–C₃-alkylaminoinclude, but are not limited to, methylamino, dimethylamino, ethylamino,diethylamino, and propylamino.

The term “alkylamino” refers to a group having the structure —NH(C₁–C₁₂alkyl) where C₁–C₁₂ alkyl is as previously defined.

The term “dialkylamino” refers to a group having the structure —N(C₁–C₁₂alkyl) (C₁–C₁₂ alkyl), where C₁–C₁₂ alkyl is as previously defined.Examples of dialkylamino are, but not limited to, dimethylamino,diethylamino, methylethylamino, piperidino, and the like.

The term “alkoxycarbonyl” represents an ester group, i.e., an alkoxygroup, attached to the parent molecular moiety through a carbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, and the like.

The term “carboxaldehyde,” as used herein, refers to a group of formula—CHO.

The term “carboxy,” as used herein, refers to a group of formula —COOH.

The term “carboxamide,” as used herein, refers to a group of formula—C(O)NH(C₁–C₁₂ alkyl) or —C(O)N(C₁–C₁₂ alkyl) (C₁–C₁₂ alkyl), —C(O)NH₂,NHC(O)(C₁–C₁₂ alkyl), N(C₁–C₁₂ alkyl)C(O)(C₁–C₁₂ alkyl) and the like.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl(trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bn or —C(O)C₆H₅), and trimethylsilyl(TMS or —Si(CH₃)₃).

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protogenic organic solvent,” as used herein, refers to asolvent that tends to provide protons, such as an alcohol, for example,methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and thelike. Such solvents are well known to those skilled in the art, and itwill be obvious to those skilled in the art that individual solvents ormixtures thereof may be preferred for specific compounds and reactionconditions, depending upon such factors as the solubility of reagents,reactivity of reagents and preferred temperature ranges, for example.Further discussions of protogenic solvents may be found in organicchemistry textbooks or in specialized monographs, for example: OrganicSolvents Physical Properties and Methods of Purification, 4th ed.,edited by John A. Riddick et al., Vol. II, in the Techniques ofChemistry Series, John Wiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—, or as (D)— or (L)— for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1–19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable include,but are not limited to, nontoxic acid addition salts are salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of Formula I. Various forms of prodrugs are known in the art,for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113–191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1–38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containing,and methods of treating bacterial infections through administering,pharmaceutically acceptable prodrugs of compounds of the formula I. Forexample, compounds of formula I having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of formula I. The amino acid residuesinclude but are not limited to the 20 naturally occurring amino acidscommonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

As used herein, unless otherwise indicated, the term “bacterialinfection(s)” or “protozoa infections”; includes, but is not limited to,bacterial infections and protozoa infections that occur in mammals, fishand birds as well as disorders related to bacterial infections andprotozoa infections that may be treated or prevented by administeringantibiotics such as the compounds of the present invention. Suchbacterial infections and protozoa infections and disorders related tosuch infections include, but are not limited to, the following:pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, andmastoiditis related to infection by Streptococcus pneumoniae,Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, orPeptostreptococcus spp. Pseudomonas spp.; pharynigitis, rheumatic fever,and glomerulonephritis related to infection by Streptococcus pyogenes,Groups C and G streptococci, Clostridium diptheriae, or Actinobacillushaemolyticum; respiratory tract infections related to infection byMycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae,Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin andsoft tissue infections, abscesses and osteomyelitis, and puerperal feverrelated to infection by Staphylococcus aureus, coagulase-positivestaphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), S. pyogenes,S. agalactiae, Streptococcal groups C–F (minute-colony streptococci),viridans streptococci, Corynebacterium spp., Clostridium spp., orBartonella henselae; uncomplicated acute urinary tract infectionsrelated to infection by S. saprophyticus or Enterococcus spp.;urethritis and cervicitis; and sexually transmitted diseases related toinfection by Chlamydia trachomatis, Haemophilus ducreyi, Treponemapallidum, Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseasesrelated to infection by S. aureus (food poisoning and Toxic shocksyndrome), or Groups A, S. and C streptococci; ulcers related toinfection by Helicobacter pylori; systemic febrile syndromes related toinfection by Borrelia recurrentis; Lyme disease related to infection byBorrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitisrelated to infection by C. trachomatis, N. gonorrhoeae, S. aureus, S.pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminatedMycobacterium avium complex (MAC) disease related to infection byMycobacterium avium, or Mycobacterium intracellulare; gastroenteritisrelated to infection by Campylobacter jejuni; intestinal protozoarelated to infection by Cryptosporidium spp. odontogenic infectionrelated to infection by viridans streptococci; persistent cough relatedto infection by Bordetella pertussis; gas gangrene related to infectionby Clostridium perfringens or Bacteroides spp.; Skin infection by S.aureus, Propionibacterium acne; atherosclerosis related to infection byHelicobacter pylori or Chlamydia pneumoniae; or the like.

Bacterial infections and protozoa infections and disorders related tosuch infections that may be treated or prevented in animals include, butare not limited to, the following: bovine respiratory disease related toinfection by P. haemolytica., P. multocida, Mycoplasma bovis, orBordetella spp.; cow enteric disease related to infection by E. coli orprotozoa (i.e., coccidia, cryptosporidia, etc.), dairy cow mastitisrelated to infection by S. aureus, S. uberis, S. agalactiae, S.dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.;swine respiratory disease related to infection by A. pleuropneumoniae.,P. multocida, or Mycoplasma spp.; swine enteric disease related toinfection by E. coli, Lawsonia intracellularis, Salmonella spp., orSerpulina hyodyisinteriae; cow footrot related to infection byFusobacterium spp.; cow metritis related to infection by E. coli; cowhairy warts related to Infection by Fusobacterium necrophorum orBacteroides nodosus; cow pink-eye related to infection by Moraxellabovis, cow premature abortion related to infection by protozoa (i.e.neosporium); urinary tract infection in dogs and cats related toinfection by E. coli; skin and soft tissue infections in dogs and catsrelated to infection by S. epidermidis, S. intermedius, coagulase neg.Staphylococcus or P. multocida; and dental or mouth infections in dogsand oats related to infection by Alcaligenes spp., Bacteroides spp.,Clostridium spp., Enterobacter spp., Eubacterium spp.,Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp.,Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosomaspp., Plasmodium spp., Babesia spp., Toxoplasma spp., Pneumocystis spp.,Leishmania spp., and Trichomonas spp. or Prevotella spp. Other bacterialinfections and protozoa infections and disorders related to suchinfections that may be treated or prevented in accord with the method ofthe present invention are referred to in J. P. Sanford at al., “TheSanford Guide To Antimicrobial Therapy,” 26th Edition, (AntimicrobialTherapy, Inc., 1996).

Antibacterial Activity

Susceptibility tests can be used to quantitatively measure the in vitroactivity of an antimicrobial agent against a given bacterial isolate.Compounds are tested for in vitro antibacterial activity by amicro-dilution method. Minimal Inhibitory Concentration (MIC) isdetermined in 96 well microtiter plates utilizing the appropriateMueller Hinton Broth medium (CAMHB) for the observed bacterial isolates.Antimicrobial agents are serially diluted (2-fold) in DMSO to produce aconcentration range from about 64 μg/ml to about 0.03 μg/ml. The dilutedcompounds (2 μl/well) are then transferred into sterile, uninoculatedCAMHB (0.2 mL) by use of a 96 fixed tip-pipetting station. The inoculumfor each bacterial strain is standardized to 5×10⁵ CFU/mL by opticalcomparison to a 0.5 McFarland turbidity standard. The plates areinoculated with 10 μl/well of adjusted bacterial inoculum. The 96 wellplates are covered and incubated at 35+/−2° C. for 24 hours in ambientair environment. Following incubation, plate wells are visually examinedby Optical Density measurement for the presence of growth (turbidity).The lowest concentration of an antimicrobial agent at which no visiblegrowth occurs is defined as the MIC. The compounds of the inventiongenerally demonstrated an MIC in the range from about 64 μg/ml to about0.03 μg/ml.

All in vitro testing follows the guidelines described in the ApprovedStandards M7-A4 protocol, published by the National Committee forClinical Laboratory Standards (NCCLS).

Pharmaceutical Compositions.

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminun hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present invention,bacterial infections are treated or prevented in a patient such as ahuman or another animal by administering to the patient atherapeutically effective amount of a compound of the invention, in suchamounts and for such time as is necessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the formulae described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically exipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The pharmaceutical compositions of this invention can be administeredorally to fish by blending said pharmaceutical compositions into fishfeed or said pharmaceutical compositions may be dissolved in water inwhich infected fish are placed, a method commonly referred to as amedicated bath. The dosage for the treatment of fish differs dependingupon the purpose of administration (prevention or cure of disease) andtype of administration, size and extent of infection of the fish to betreated. Generally, a dosage of 5–1000 mg, preferably 20–100 mg, per kgof body weight of fish may be administered per day, either at one timeor divided into several times. It will be recognized that theabove-specified dosage is only a general range which may be reduced orincreased depending upon the age, body weight, condition of disease,etc. of the fish.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one of ordinary skill in theart. All publications, patents, published patent applications, and otherreferences mentioned herein are hereby incorporated by reference intheir entirety.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are:

-   -   Ac for acetyl;    -   AIBN for azobisisobutyronitrile;    -   Bu₃SnH for tributyltin hydride;    -   CDI for carbonyldiimidazole;    -   dba for dibenzylidene acetone;    -   dppb for diphenylphosphino butane;    -   DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;    -   DEAD for diethylazodicarboxylate;    -   DMAP for dimethylaminopyridine;    -   DMF for dimethyl formamide;    -   DPPA for diphenylphosphoryl azide;    -   EtOAc for ethyl acetate;    -   MeOH for methanol;    -   NaN(TMS)₂ for sodium bis(trimethylsilyl)amide;    -   NMMO for N-methylmorpholine N-oxide;    -   TEA for triethylamine;    -   THF for tetrahydrofuran;    -   TPP or PPh₃ for triphenylphosphine;    -   MOM for methoxymethyl;    -   Boc for t-butoxycarbonyl;    -   Bz for benzyl;    -   Ph for phenyl;    -   POPd for dihydrogen        dichlorobis(di-tert-butylphosphinito-κP)palladate(II);    -   TBS for tert-butyl dimethylsilyl; or    -   TMS for trimethylsilyl.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared.

A preferred intermediate for the preparation of compounds represented byformula I is a compound represented by formula IX as illustrated below

wherein R₆ and R₂′ are as previously defined.

A second preferred intermediate for the preparation of compoundsrepresented by formula I is a compound represented by formula X asillustrated below

where X, Y, R₂′, R₄″ and R₆′ are as previously defined.

Schemes 1–4 describe processes for the preparation of intermediateswhich are useful in the preparation of compounds according to theinvention.

Compounds of formula (1-2), which are useful as the starting materialsfor the preparation of compounds of the present invention, may besynthesized as detailed in Schemes 1 and 2 below. An erythromycinderivative (1-2) is prepared from erythromycin using the proceduresdescribed in U.S. Pat. Nos. 4,990,602; 4,331,803; 4,680,386; 4,670,549;and European Patent Application EP 260,938.

The erythromycin derivative of formula (1-2), is then reacted with analkylating agent of the formula:R₁₃—OC(O)O—CH₂[C═CH R₁₁]CH₂—OC(O)—OR₁₃  (1-3)where R₁₃ is C₁–C₁₂-alkyl and R₁₁ is as previously defined.

Most palladium (0) catalysts are expected to work in this process. Somepalladium (II) catalysts, such as palladium (II) acetate, which isconverted into a palladium (0) species in-situ by the actions of aphosphine, will work as well. See, for example, Beller et al. Angew.Chem. Int. Ed. Engl., 1995, 34 (17), 1848. The palladium catalyst can beselected from, but not limited to, the group consisting of palladium(II) acetate, tetrakis(triphenylphospine)palladium (0),tris(dibenzylideneacetone)dipalladium,tetradi(benzylideneacetone)dipalladium and the like. Palladium on carbonand palladium (II) halide catalysts are less preferred than otherpalladium catalysts for this process.

Suitable phosphines include, but are not limited to, triphenylphosphine,bis(diphenylphosphino)methane, bis(diphenylphosphino)ethane,bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane,bis(diphenylphosphino)pentane, and tri(o-tolyl)phosphine, and the like.

The reaction is carried out in an aprotic solvent, preferably atelevated temperature, for example, at or above 50° C. Suitable aproticsolvents include, but are not limited to, tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone,hexamethylphosphoric triamide, 1,2-dimethoxyethane, methyl-tert-butylether, heptane, acetonitrile, isopropyl acetate and ethyl acetate. Themost preferred solvents are tetrahydrofuran or toluene.

The alkylating agents useful in the processes of the invention aredi-carbonates (1-3). Generally, the alkylating agents have the formula(1-3), previously described. The preferred alkylating agents are thosewherein R₁₃ is a tert-butyl, isopropyl or isobutyl group. The alkylatingreagents are prepared by reaction of a di-ol with a wide variety ofcompounds for incorporating the di-carbonate moiety. The compoundsinclude, but are not limited to, tert-butyl chloroformate, di-tert-butyldicarbonate, and 1-(tert-butoxycarbonyl)imidazole and the reaction iscarried out in the presence of an organic or an inorganic base. Thetemperature of the reaction varies from about −30° C. to about 30° C.Preferably, the alkylating reagent is di-tert-butyl dicarbonate.

An alternative method of converting the alcohol into the carbonateinvolves treating the alcohol with phosgene or triphosgene to preparethe chloroformate derivative of the di-ol. The di-chloroformatederivative is then converted into the di-carbonate by the methodsdescribed in Cotarca, L., Delogu, P., Nardelli, A., Sunijic, V,Synthesis, 1996, 553. The reaction can be carried out in a variety oforganic solvents such as dichloromethane, toluene, diethyl ether, ethylacetate and chloroform in the presence of a base. Examples of suitablebases include, but are not limited to, sodium hydroxide, potassiumhydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate,ammonium carbonate, dimethylaminopyridine, pyridine, triethylamine andthe like. The temperature conditions can vary from 0° C. to about 60° C.The reaction typically takes about 3 to 5 hours to run to completion.

The cladinose moiety of macrolide (1-4) is removed either by mild acidhydrolysis or by enzymatic hydrolysis to give compounds of formula(1-5). Representative acids include dilute hydrochloric acid, sulfuricacid, perchloric acid, chloroacetic acid, dichloroacetic acid ortrifluoroacetic acid. Suitable solvents for the reaction includemethanol, ethanol, isopropanol, butanol and the like. Reaction times aretypically 0.5 to 24 hours. The reaction temperature is preferably −10°C. to 80° C.

Compounds of formula (1-4), where R₆ is an acetyl group, can beconverted into the corresponding imine as outlined in Scheme 2.Selective deprotection of the oxime is typically accomplished viaalkaline hydrolysis in protic solvents. Representative alkali compoundsinclude lithium hydroxide, sodium hydroxide, potassium hydroxide, andthe like. Suitable solvents include, but are not limited to,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, isopropanol, ethanol,butanol and mixtures there of. The reaction temperature is preferably 0°to 35° C. and reaction time is preferably 0.5 to 8 hours.

In a like fashion, simultaneous deprotection of both the oxime and the2′ hydroxyl can be accomplished under a variety of conditions.Conditions for deprotection include, but not limited to, treating withan alcoholic solvent from room temperature to reflux, or treatment witha primary amine, such as butylamine. Alcoholic solvents preferred forthe deprotection are methanol and ethanol. A more thorough discussion ofthe procedures, reagents and conditions for removing protecting groupsis described in literature, for example, by T. W. Greene and P. G. M.Wuts in “Protective Groups in Organic Synthesis” 3^(rd) ed., John Wiley& Son, Inc, 1999.

Deoxygenation of compounds of formula (2-1) under reducing conditionsgives the macrolide imine of formula (2-2). Many reducing agents can beused to effect this transformation including, but not limited to,lithium aluminum hydride, titanium trichloride, borane, and varioussulfides such as sodium hydrogen sulfide and sodium nitrite. For a moredetailed account of oxime reduction see J. March in “Advanced OrganicChemistry” 4^(th) ed., Wiley & Son, Inc, 1992.

A particularly useful method for the reduction of oximes to thecorresponding imine uses a sulfite reducing agent, such as sodiumhydrogensulfite, under acidic conditions, typically in protic solvents.Representative acids include, but are not limited to, acetic acid,formic acid, dilute hydrochloric acid, dilute phosphoric acid, dilutesulfuric acid, and the like. Suitable protic solvents include, but arenot limited to, mixtures of water and methanol, ethanol, isopropanol, orbutanol. The reaction is typically carried out at 500 to 110° C.,preferably for between 1 and 10 hours.

Hydrolysis of the cladinose moiety can be accomplished as previouslydescribed in scheme 1 to give compounds of formula (2-3)

Alternatively compounds of formula (2-3) can be formed directly fromcompounds of formula (2-1) via treatment with TiCl₃ in alcoholicsolvents, preferably methanol or ethanol

Imines of formula (2-3) can be acylated under basic conditions using asuitable acylating agent in an aprotic solvent. Typical acylating agentsinclude, but are not limited to, acetyl chloride, acetic anhydride,benzoyl chloride, benzoic anhydride, and benzyl chloroformate.

Examples of aprotic solvents are dichloromethane, chloroform,tetrahydrofuran, N-methylpyrrolidinone, dimethylsulfoxide,N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide, a mixture thereof or a mixture of one of these solvents withether, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-dichloroethane,acetonitrile, ethyl acetate, acetone and the like. Aprotic solvents donot adversely affect the reaction. Preferably, the solvent is selectedfrom dichloromethane, chloroform, N,N-dimethylformamide,tetrahydrofuran, N-methylpyrrolidinone or mixtures thereof.

Typical bases include, but are not limited to, pyridine, triethylamine,diisopropyl ethylaamine, N-methyl morpholine, N-methylpyrrolidine,2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene. For a more extensivediscussion of acylating conditions see, for example, T. W. Greene and P.G. M. Wuts in “Protective Groups in Organic Synthesis” 3^(rd) ed., JohnWiley & Son, Inc, 1999.

Stepwise formation of the 6–11 bridged macrolides is also possible asoutlined in Scheme 3. In a similar manner as previously described, theprocedure involves reacting a compound of formula (1-4) with a suitablealkylating agent. As before, the erythromycin derivative of formula(1-4) is reacted with an alkylating agent of the formula:R₁₃—OC(O)O—CH₂[C═CHR₁₁]CH₂—O—R_(p)  (3-1)where R₁₃ is C₁–C₁₂-alkyl, and R₁₁ and R_(p) are as previously defined.

As discussed previously, most palladium (0) catalysts are expected towork in this process and the reaction is carried out in an aproticsolvent, preferably at elevated temperature, preferably at or above 50°C. The most preferred solvents are tetrahydrofuran and toluene.

The alkylating agents useful in the process of the invention are themixed silyl ether carbonates (3-1). Generally, the alkylating agentshave the formula (3-1), previously described. The preferred alkylatingagents are those wherein R₁₃ is tert-butyl, isopropyl or isobutyl andR_(p) is tert-butyl dimethyl silyl, triisopropyl silyl, tert-butyldiphenyl silyl or the like.

The alkylating reagents of formula (3-1) are prepared by reaction of adiol sequentially with a wide variety of compounds for incorporating thecarbonate moiety, followed by a wide variety of compounds forincorporating the silyl moiety. Alkylating reagents include, but notlimited to, tert-butyl chloroformate, di-tert-butyl dicarbonate, and1-(tert-butoxycarbonyl)imidazole; where as silylating reagents include,but are not limited to tert-butyl dimethyl silyl chloride, tert-butyldimethyl silyl triflate, tert-butyl dimethyl silyl cyanide, andtert-butyl dimethyl silyl imidazole. Both reactions are carried out inthe presence of an organic or an inorganic base. The temperature of thereactions vary from about −30° C. to about 30° C. Preferably, thealkylating reagent is di-tert-butyl dicarbonate and the silylatingreagent is tert-butyl dimethyl silyl chloride.

The free oxime (−3) is prepared using essentially the same procedure asfor the deprotection of oxime (1-4) where R₆ is Ac in Scheme 2.

Compounds of formula (3-4) can be formed directly from compounds offormula (3-3) by the application of the previously described procedurefor the reduction of oximes of formula (2-1) to the corresponding imineof formula (2-2).

The protecting group (Rp) is then removed from the hydroxyl of thecompound of formula 3-4) using the appropriate conditions as outlined inT. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicSynthesis” 3^(rd) ed., John Wiley & Son, Inc, 1999. For example, whenthe protecting group is TBS, tetra-n-butyl ammonium fluoride,hydrofluoric acid or trifluoro acetic acid may be used. Using standardconditions, the primary hydroxyl is converted to the tert-butylcarbonate, and subsequently the 11-hydroxyl group is alkylated by meansof a palladium (0) catalyst as described previously. In this waycompounds of formula (3-6) can be prepared readily.

Removal of the cladinose sugar is accomplished as previously describedin Scheme 1 to give a compound of formula (1-5).

Compounds according to the invention (5-1) may be prepared by oxidationof the secondary alcohol using Dess Martin periodinane as the oxidant.The reaction is typically run in an aprotic solvent at 0° to 25° C. Thereaction time is typically between 1 and 12 hours.

Alternatively the oxidation can be accomplished using pyridiniumchlorochromate, sulfur trioxide pyridine complex in dimethyl sulfoxide,tetra-n-propyl ammonium perruthenate and N-methyl morpholine N-oxide,Swern oxidation or the like. A more thorough discussion of the oxidationof secondary alcohols can be found in J. March in “Advanced OrganicChemistry” 4^(th) ed., Wiley & Son, Inc, 1992.

Scheme 5 illustrates another process of the invention for thepreparation of compounds according to the invention. Conversion ofalkene (6-1) into ketone (6-2) can be accomplished by exposure of thealkene to ozone followed by decomposition of the ozonide with theappropriate reducing agent, as outlined in Scheme 3. The reaction istypically carried out in an inert solvent such as, but not limited to,methanol, ethanol, ethyl acetate, glacial acetic acid, chloroform,methylene chloride or hexanes or mixtures thereof, preferably methanol,preferably at −78° to −20° C. Representative reducing agents are, forexample, triphenylphosphine, trimethyl phosphite, -thiourea, anddimethyl sulfide, preferably triphenylphosphine. A more thoroughdiscussion of ozonolysis and the conditions there for can be found in J.March “Advanced Organic Chemistry” 4^(th) ed., Wiley & Son, Inc, 1992.

An alternative method for the preparation of ketone (6-2) involvesdihydroxylation of the alkene followed by diol cleavage. The glycol(6-3) is first prepared by reacting alkene (6-1) with osmium tetroxide.This reaction can be carried out with stochiometric amounts of osmiumtetroxide, or, if an oxidant such as hydrogen peroxide, tert-butylhydroperoxide, or N-methylmorpholine-N-oxide is present, with catalyticamounts of osmium tetroxide. These reactions can be carried out in avariety of solvents including: 1,4-dioxane, tetrahydrofuran,tert-butanol and diethyl ether, preferably at 0° C.

The glycol can be cleaved by a variety of reagents including, but notlimited to, periodic acid, lead tetraacetate, manganesedioxide,potassium permanganate, sodium metaperiodate, and N-iodosuccinamide.Depending on the cleavage reagent, a variety of solvents can be used.Preferably the cleavage reagent is sodium metaperiodate, the solvent ispreferably a mixture of ethanol, methanol, acetone, or 1,4-dioxane andwater and the reaction temperature is 0 to 25° C.

Scheme 6 illustrates the procedure by which compounds of formula (7-1)may be converted to compounds of formula (7-2) by treatment with ahalogenating reagent. This reagent acts to replace a hydrogen atom witha halogen atom at the C-2 position of the ketolide. Various halogenatingreagents may be suitable for this procedure.

Fluorinating reagents include, but are not limited to,N-fluorobenzenesulfonimide in the presence of base, 10% F₂ in formicacid, 3,5-dichloro-1-fluoropyridinium tetrafluoroborate,3,5-dichloro-1-fluoropyridinium triflate, (CF₃SO₂)₂NF,N-fluoro-N-methyl-p-toluenesulfonamide in the presence of base,N-fluoropyridinium triflate, N-fluoroperfluoropiperidine in the presenceof base.

Chlorinating reagents include, but are not limited to, hexachloroethanein the presence of base, CF₃CF₂CH₂ICl₂, SO₂Cl₂, SOCl₂, CF₃SO₂Cl in thepresence of base, Cl₂, NaOCl in the presence of acetic acid.

Brominating reagents include, but are not limited to, Br₂.pyridine.HBr,Br₂/acetic acid, N-bromosuccinimide in the presence of base,LDA/BrCH₂CH₂Br, or LDA/CBr₄

A suitable iodinating reagent is N-Iodosuccinimide in the presence ofbase, or I₂, for example

Suitable bases for the halogenating reactions requiring them arecompounds such as alkali metal hydrides, such as NaH and KH, or aminebases, such as LDA or triethylamine, for example. Different reagents mayrequire different type of base, but this is well known within the art.

A preferred halogenating reagent is N-fluorobenzenesulfonimide in thepresence of sodium hydride.

Suitable solvents are dimethylformamide, dimethyl sulfoxide,pyrrolidinone and the like.

It will be appreciated by one skilled in the art that compounds offormula 7-1) or 7-2) can be substituted for compounds of formula (−1) or(6-2) in the preceding examples if the corresponding C-2 halogenatedproduct is desired.

For ease of illustration, in Scheme 7 only the 6–11 bridged moiety ofeach particular compound according to formula I will be shown, it beingunderstood that it is intended to illustrate a compound according toformula I with the specified bridged moiety. Compounds according to theinvention of the formulas (6-1) and (6-2) can be further functionalizedin a variety of ways. Scheme 7 details a procedure for the conversion ofthe ketone (6-2) into an oxime of formula (7-7). Oxime formation can beaccomplished, using the appropriate substituted hydroxylamine, undereither acidic or basic conditions in a variety of solvents.Representative acids include, but are not limited to, hydrochloric,phosphoric, sulfuric, p-toluenesulfonic, and pyridinium p-toluenesulfonate. Likewise, bases that are useful are, for example,triethylamaine, pyridine, diisopropylethyl amine, 1,5-lutidine, and thelike. Appropriate solvents include, but are not limited to, methanol,ethanol, water, tetrahydrofuran, 1,2-dimethoxyethane, and ethyl acetate.Preferably the reaction is carried out in ethanol using triethylamine asthe base. Reaction temperature is generally 25° C. and reaction time is1 to 12 hours.

Ketone (6-2) can also be further utilized by conversion into the amine(2-9) via a reductive amination protocol. Thus, the ketone is treatedwith an amine in the presence of a reducing agent to obtain the productamine (7-9). The reaction can be carried out either with or withoutadded acid. Examples of acids that are commonly used include,hydrochloric, phosphoric, sulfuric, acetic, and the like. Reducingagents that effect reductive amination include, but are not limited to,hydrogen and a catalyst, zinc and hydrochloric acid, sodiumcyanoborohydride, sodium borohydride, iron petnatcarbonyl, and alcoholicpotassium hydroxide. Generally alcoholic solvents are used. Thepreferred conditions use sodium cyanoborohydride in methanol with addedacetic acid.

A still further way to functionalize ketone (6-2) is via addition ofGrignard reagents to form alcohols of formula (7-8). Scheme 8 depictsthis protocol. The requisite Grignard reagents are readily available viathe reaction of a variety of alkyl or aryl halides with magnesium understandard conditions (see B. S. Fumiss, A. J. Hannaford, P. W. G. Smith,A. R. Tatchell “Vogel's Textbook of Practical Organic Chemistry” 5^(th)ed., Longman, 1989). The addition is performed in an inert solvent,generally at low temperature. Suitable solvents include, but are notlimited to tetrahydrofuran, diethylether, 1,4-dioxane,1,2-dimethoxyethane, and hexanes. Preferably the solvent istetrahydrofuran or diethylether. Preferably the reaction is run at −78°to 0° C.

In a similar way, reaction with other organometallic reagents gives riseto alcohols of type (7-8). Examples of organometallic reagents that maybe used include, but are not limited to, organo-aluminum,organo-lithium, organo-cerium, organo-zinc, organo-thallium, andorgano-boron reagents. A more thorough discussion of organometallicreagents can be found in B. S. Furniss, A. J. Hannaford, P. W. G. Smith,A. R. Tatchell “Vogel's Textbook of Practical Organic Chemistry” 5^(th)ed., Longman, 1989.

Furthermore, alcohols of type (2-14) can be prepared by reduction of thecorresponding ketone (6-2) under a variety of conditions. (see Hudlicky,M. Reductions in Organic Chemistry, Ellis Horwood Limited: Chichester,1984). The alcohols thus derived can be further modified to givecompounds of type (7-15). Processes to generate compounds of formula(7-15) include, but are not limited to: alkylation of the alcohol withan electrophile or conversion of the alcohol into a leaving group suchas a triflate, tosylate, phosponate, halide, or the like followed bydisplacement with a heteroatom nucleophile (e.g. an amine, alkoxide,sulfide or the like).

It will be appreciated by one skilled in the art, that the unsaturatedcompounds represented by compounds (6-1) and (6-2) can be reduced toform the corresponding saturated compound (see Hudlicky, M. Reductionsin Organic Chemistry, Ellis Horwood Limited: Chichester, 1984).

The glycol (7-5) can be prepared by reacting alkene (6-1) with osmiumtetroxide. This reaction can be carried out either with stochiometricamounts of osmium tetroxide, or, if a oxidant such as hydrogen peroxide,tert-butyl hydroperoxide, or N-methylmorpholine-N-oxide are present,with catalytic amounts of osmium tetroxide. These reactions can be runin a variety of solvents including: 1,4-dioxane, tetrahydrofuran,tert-butanol and diethyl ether, preferably at 0° C. The glycols thusderived can be further modified to give compounds of type 7-12) by, forinstance, selective alkylation of the primary alcohol with anelectrophile (see B. S. Fumiss, A. J. Hannaford, P. W. G. Smith, A. R.Tatchell “Vogel's Textbook of Practical Organic Chemistry” 5^(th) ed.,Longman, 1989).

Epoxides of type (7-10) can be prepared by the conversion of the primaryalcohol into a leaving group such as a triflate, tosylate, phosponate,halide, or the like, followed by intramolecular nucleophillicdisplacement (see Tetrahedron Lett., 1983, 661–664). Epoxides of formula(7-10) can be further funtionalized via ring opening with a variety ofnucleophiles. Representative nucleophiles include, but are not limitedto, amines, alkoxides, sulfides, organometallic reagents and the like.Reactions can be carried out in the presence or absence of Lewis acidactivators such as silver carbonate, silver triflate, boron trifluorideetherate, aluminum trichloride and the like. (see (a) J. Med Chem.,1997, 2762–2769, (b) J. Amer. Chem. Soc., 1999, 10251–10263, (c)Tetrahedron Lett., 2000, 4229–4234)

Compounds of the invention according to formula (6-1) are also capableof further functionalization to generate compounds of the presentinvention. Alkene (6-1) can be treated with an aryl halide or aryltriflate in the presence of a palladium catalyst [Pd(0) or Pd(II)] toprovide compound (9-3): (See (a) Heck, Palladium Reagents in OrganicSynthesis, Academic Press: New York, 1985, Chapter 1; (b) Sonogashira,Comprehensive Organic Synthesis, Volume 3, Chapters 2,4; (c)Sonogashira, Synthesis 1977, 777.). Under the Heck coupling conditions,regioisomers and stereoisomers of the double bond are possible.Alternatively, compound (6-1) can undergo a cross metathesis reactionwith vinyl aromatic derivatives using ruthenium catalysts to givecompounds of formula (9-2) (see (a) J. Org. Chem. 2000, 65, 2204–2207;(b) Reviews: Synlett. 1999, 2, 267; (c) Reviews: Ivin, K. J.; Mol. J. C.Olefin Metathesis and Metathesis Polymerization, 2^(nd) ed.; AcademicPress: New York, 1997; (d) J. Org. Chem. 1999, 64, 4798–4816; (e) Angew.Chem., rt. Ed. Engl. 1997, 36, 2036–2056; (f) Tetrahedron 1998, 54,4413–4450).

It will be appreciated that ketones of formula (6-2) can be transformedinto alkenes of formula (9-2) and (8-1) via Wittig reaction with theappropriate phosphonium salt in the presence of a base. (see (a) Burke,Tetrahedron Lett., 1987, 4143–4146, (b) Rathke and Nowak, J. Org. Chem.,1985, 2624–2626, (c) Maryanoff and Reitz, Chem. Rev., 1989, 863–927.Furthermore, vinyl halides of formula (8-1) can be functionalized bySonogashira coupling with alkynes in the presence of a palladiumcatalyst, a copper halide and an amine base to give compounds of formula(8-2) (see (a) Sonogashira, Comprehensive Organic Synthesis, Volume 3,Chapters 2,4; (b) Sonogashira, Synthesis 1977, 777.). In a similarmanner, alkenes of formula (9-2) can be obtained from vinyl halides(8-1) via Suzuki cross coupling with organoboron reagents in thepresence of a palladium catalyst and a base, or via Stille crosscoupling with organostananes in the presence of a palladium catalyst.(see (a) Suzuki, J. Organomet. Chem. 1999, 576,147–168, (b) Stille,Angew. Chem. Int. Ed. Engl., 1986, 508–524 (c) Farina, J. Am. Chem.Soc., 1991, 9585–9595).

It will be appreciated by one skilled in the art, that the unsaturatedcompounds represented by compounds (9-2) and (8-2) can be reduced toform the corresponding saturated compound (see Hudlicky, M. Reductionsin Organic Chemistry, Ellis Horwood Limited: Chichester, 1984).

It will be appreciated that compounds of the present invention includemodification of the 3′ N of compounds of the formula (10-1). Compoundsof formula (10-2), where W is as previously defined, can be made via themethods delineated in U.S. Pat. Nos. 6,034,069 and 6,387,885.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH₂, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H, andR₂′═Ac

Step 1a: Compound of Formula 1-2: R₆═Ac, R₂′═Ac and R₄″═Ac

To a solution of erythromycin A oxime (74.9 g, 0.1 mol) in 400 ml THFwas added acetic anhydride (35.9 ml, 0.38 mol), triethylamine (55.7 ml,0.4 mol) and DMAP (3.7 g, 0.03 mol) at room temperature. The mixture wasstirred at room temperature for 16 hours and was condensed to ˜200 ml,diluted with 300 ml of ethyl acetate and the resulting mixture washedwith NaHCO₃ (Sat.) (500 ml×4) and brine (500 ml) and dried on anhydroussodium sulfate. The solvent was evaporated and the residue wasrecrystallized from ethyl acetate to give title compound (78 g).

MS (ESI) m/z 875 (M+H)⁺. ¹³C NMR(CDCl₃): δ 178.5, 175.4, 170.6, 170.2,168.2, 100.2, 96.1, 83.3, 79.3, 78.7, 75.2, 74.5, 72.9, 70.0, 67.6,63.4, 63.2, 60.6, 49.5, 44.7, 40.9, 35.4, 31.8, 28.5, 22.8, 21.7, 21.6,21.5, 21.3, 21.2, 21.1, 19.9, 18.6, 18.4, 16.7, 14.9, 14.4, 14.3, 10.8,9.2

Step 1b: Compound of Formula 1-3: R₁₁═H and R₁₃=t-Bu:

To a solution of 2-methylene-1,3-propane diol (5.28 g, 0.06 mmol) anddi-tert-butyl dicarbonate (35 g, 0.16 mol) in 150 ml of dichloromethanewas added 6N NaOH (70 ml) and tetrabutylammoniahydrogensulfate (3.4 g,10 mmol). The mixture was stirred at room temperature overnight. Theorganic layer was separated, washed with NaHCO₃ (200 ml×3) and brine(200 ml), dried over anhydrous MgSO₄, concentrated and dried over vacuumto give the title compound.

¹H NMR (CDCl₃): δ 5.20(s, 2H); 4.44(s, 4H); 1.18(s, 18H). ¹³CNMR(CDCl₃): δ 153.3, 138.5, 117.3, 82.3, 66.9, 27.8.

Step 1c: Compound of Formula 1-4: R₆═Ac, R₁₁═H, R₂′═Ac and R₄″═Ac

To a solution of erythromycin oxime 2′,4″,9-triacetate from Step 1a (112g, 128 mmol), the compound from step 1b (44.3 g, 154 mmol) and dppb(1.71 g, 4 mmol) in THF (500 ml), was added Pd₂(dba)₃ (1.83 g, 2 mmol)under nitrogen. The mixture was refluxed for 5 hours and concentrated.The residue was purified by flash chromatography (SiO₂hexane:acetone/2:1) to give the title compound. (110 g).

MS (ESI) m/z 927.64 (M+H)⁺¹³C NMR(CDCl₃): δ 176.5, 175.9, 170.7, 170.1,169.9, 141.6, 124.7, 100.4, 96.0, 79.1, 78.7, 78.2, 78.0, 77.4, 76.5,73.5, 73.0, 72.4, 72.1, 67.8, 66.1, 63.4, 63.3, 49.6, 44.1, 41.2, 40.9,37.3, 35.4, 35.1, 31.3, 29.5, 28.5, 27.1, 23.4, 21.7, 21.3, 21.1, 20.9,20.3, 18.8, 18.3, 17.4, 15.7, 13.4, 12.7, 8.6.

Step 1d: Compound of Formula 2-1: R₁₁═H, R₂′═H and R₄″═Ac

A solution of the compound of Step 1c (32 g) in 400 ml methanol wasrefluxed for 48 hours and then concentrated. The residue was purified byflash chromatography (SiO₂, CH₂Cl₂:2M ammonia in methanol=95:5) to givethe title compound (28.5 g).

MS (ESI) m/z 843 (M+H)⁺¹³C NMR(CDCl₃): δ 176.2, 170.8, 168.8, 142.0,124.2, 102.5, 95.9, 79.4, 78.7, 78.1, 78.0, 76.6, 73.0, 71.8, 71.1,68.2, 65.6, 63.2, 49.7, 44.2, 41.7, 40.5, 37.7, 35.0, 34.4, 29.3, 25.8,23.5, 21.9, 21.3, 21.1, 19.0, 18.1, 17.5, 15.3, 13.2, 12.7, 8.7.

Step 1e: Compound of Formula 2-2: R₁₁═H and R₂′═H

Titanium trichloride (40 ml, 20% in 3% hydrochloric acid) was addeddropwise over 10 minutes to a stirred solution of the compound from Step1d (9.5 g, 11.3 mmol) and ammonium acetate (17.4 g, 226 mmol) in 120 mlof methanol at 0° C. The reaction mixture was allowed to warm up to roomtemperature and stirred over night. The pH of the reaction mixture wasadjusted to pH=10 by slow addition of 3N aqueous sodium hydroxide. Theaqueous solution was extracted with ethyl acetate (200 ml) and theorganic phase was washed once with saturated sodium bicarbonate (200ml), dried over sodium sulfate and solvent was removed in vacuo. Theresidue was purified by flash chromatography (SiO₂, CH₂Cl₂:2M ammonia inmethanol/95:5) to give the title compound (3.0 g).

MS (EST) m/z: 627 (M+H). ¹³C-NMR(100 MHz, CDCl₃): δ 188.5, 176.0, 143.9,118.9, 106.9, 90.8, 79.8, 79.6, 79.2, 77.4, 75.9, 75.3, 70.8, 70.4,65.8, 65.3, 44.6, 42.1, 40.4, 38.6, 36.4, 35.3, 28.2, 22.9, 21.5, 20.0,19.7, 16.8, 15.1, 14.9, 11.5, 8.3.

Step 1f: Compound of Formula 1-5: V═N—O—Ac, R₁₁═H and R₂′═Ac

To a solution of the compound from Step 1e (3 g, 4.8 mmol) in 40 ml ofdichloromethane was added acetic anhydride (1.36 ml, 14.4 mmol) andtriethyl amine (2.8 ml, 20 mmol). The mixture was stirred at roomtemperature for 4 hours. The solvent was removed under vacuum and theresidue was purified by flash chromatography (SiO₂, hexane:acetone/1:1)to give the title compound (2.9 g).

MS (ESI) m/z 711.50 (M+H)⁺¹³C NMR(CDCl₃): δ 184.7, 176.9, 174.9, 170.1,141.9, 122.2, 99.4, 81.2, 79.0, 77.8, 77.7, 76.1, 73.5, 71.7, 68.8,65.7, 63.2, 43.7, 40.8, 39.9, 38.2, 36.2, 35.6, 31.0, 25.5, 23.2, 21.6,21.2, 19.9, 19.5, 17.1, 15.8, 14.7, 11.8, 7.9.

Step 1 g: Compound of Formula I: A and B Taken Together with the CarbonAtom to Which They are Attached are C═CH₂, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H andR₂′═Ac

To a solution of the compound from Step 1f (2.9 g, 4.08 mmol) in 40 mldichloromethane was added Dess-Martin reagent (1.9 g, 4.5 mmol) at roomtemperature. The mixture was stirred at room temperature for 2 hours.The reaction was quenched with sodium bicarbonate (50 ml) and Na₂S₂O₃ (2g). The organic phase was separated and washed with brine (50 ml). Thesolvent was removed under vacuum and the residue was purified onchromatography (hexane:acetone/1:1) to give the title compound (2.0 g).

MS (ESI) m/z 709.28 (M+H)⁺¹³C NMR(CDCl₃): 205.8, 184.5, 177.4, 170.0,168.0, 141.2, 124.3, 100.5, 79.2, 78.1, 77.5, 76.2, 74.5, 73.4, 72.1,71.4, 69.0, 65.7, 63.1, 50.5, 45.5, 40.3, 38.5, 30.7, 25.3, 23.4, 21.5,21.1, 20.0, 19.4, 17.4, 15.4, 13.8, 13.3, 12.5.

Example 2

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH₂, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H andR₂′═H

A solution of the compound of Example 1 (2.0 g, 2.82 mmol) in 40 mlmethanol was refluxed for 5 hours. The solvent was evaporated to givethe crude title compound.

MS (ESI) m/z 667.40 (M+H)⁺¹³C NMR(CDCl₃): 205.9, 184.5, 177.5, 168.1,141.3, 124.4, 103.1, 79.1, 78.2, 77.5, 76.2, 75.6, 73.4, 72.1, 70.4,69.6, 66.0, 65.7, 50.5, 46.2, 40.4, 38.7, 28.5, 25.4, 23.4, 21.4, 20.0,19.6, 17.5, 15.4, 13.9, 13.5, 12.6.

Example 3

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═O, X and Y Taken Together with the CarbonAtom to Which They Attached are C═N—Ac, L═CH₂CH₃, Z═H and R₂′═H

A solution of the crude compound from Example 2 in methanol (10 ml) anddichloromethane (30 ml) was cooled to −78° C. and ozone was bubbledthrough the reaction until the solution became light blue. Then nitrogenwas bubbled through the reaction mixture to remove excess ozone andtriphenyl phosphine (5.64 mmol) was added. The solution was allowed towarm to room temperature over 1 hour. The solvent was evaporated and theresidue was dissolved in 40 ml of THF. Triphenyl phosphine (5.64 mmol)was added and the mixture was refluxed overnight. The solvent wasremoved under vacuum and the residue was purified by flashchromatography (SiO₂, CH₂Cl₂:2M ammonia in methanol=95:5) to give thetitle compound (1.5 g).

MS (ESI) m/z 669.38 (M+H)⁺¹³C NMR(CDCl₃): δ 205.6, 205.1, 184.4, 175.8,169.7, 102.5, 80.2, 79.0, 78.8, 77.5, 76.1, 75.8, 75.5, 70.4, 69.7,68.6, 66.0, 50.9, 45.9, 40.4, 39.7, 38.8, 36.6, 28.4, 25.5, 23.1, 21.4,19.9, 19.7, 17.2, 15.4, 14.2, 13.1, 11.6.

Example 4

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O—CH₂-Ph, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H andR₂′═.H

A solution of the crude compound from Example 3 (34 mg, 0.05 mmol),benzyl hydroxylamine (16 mg, 0.1 mmol) and pyridine (0.2 mmol) in 4 mlethanol was stirred at room temperature for 1 hour. The reaction mixturewas concentrated and purified by flash chromatography (SiO₂, CH₂Cl₂:2Mammonia in methanol=95:5) to give the title compound (35 mg, 3:1 cis andtrans mixture).

MS (ESI) m/z 774.48 (M+H)⁺.

Example 5

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O—CH₂—(3-pyridyl), X and Y TakenTogether with the Carbon Atom to Which They are Attached are C═N—Ac,L═CH₂CH₃, Z═H and R₂′═H

Step 5a: N-phthaloyl-O-pyridin-3-ylmethyl-hydroxylamine

To a solution of N-hydroxyphthalimide (653 mg, 4 mmol) and sodiumcarbonate (848 mg, 8 mmol) in DMF-CH₃CN—H₂O (5 ml/1 ml/5 ml) was added3-(bromomethyl)pyridine hydrobromide (1.01 g, 4 mmol), portion byportion, at room temperature. The mixture was stirred at roomtemperature for 2 hours, diluted with ethyl acetate (30 ml), washed with5% of Trisamine and dried over Na₂SO₄. The solvent was removed undervacuum and the residue was purified by silica gel chromatography(hexane:ethyl acetate/3:2) to give the title compound (0.8 g).

Step 5b: Compound of Formula I: A and B Taken Together with the CarbonAtom to Which They are Attached are C═N—O—CH₂—(3-pyridyl), X and Y TakenTogether with the Carbon Atom to Which They are Attached are C═N—Ac,L═CH₂CH₃, Z═H and R₂′═H

To a solution of N-phthaloyl-O-pyridin-3-ylmethyl-hydroxylamine (81.3mg, 0.32 mmol) in 5 ml of ethanol was added hydrazine hydrate (12 mg,0.24 mmol) at room temperature. The mixture was stirred at 40° C. for 2hours and then cooled to room temperature. Acetic acid (7 μl, 0.12 mmol)was added followed by the compound of Example 3 (27 mg, 0.04 mmol). Themixture was stirred at 60° C. for 12 hours. The solvent was removedunder vacuum and the residue was purified by flash chromatography (SiO₂,CH₂Cl₂:2M ammonia in CH₃OH=95:5) to give the title compound (24 mg).

MS (ESI) m/z 774.48 (M+H)⁺.

Example 6

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O—CH₂—(2-pyridyl), X and Y TakenTogether with the Carbon Atom to Which They are Attached are C═N—Ac,L═CH₂CH₃, Z═H and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 5, 81.3 mg (0.32 mmol) ofN-phthaloyl-O-pyridin-2-ylmethyl-hydroxylamine was reacted with 12 mg(0.24 mmol) of hydrazine hydrate. Then 7 μl of glacial acetic acid wasadded followed by 27 mg (0.04 mmol) of the compound of Example 3. Afterisolation, 23 mg of the desired product were obtained.

MS: (ESI) m/z 774.48 (M+H)⁺.

Example 7

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O—CH₂—(3-quinolyl), X and Y TakenTogether with the Carbon Atom to Which They are Attached are C═N—Ac,L═CH₂CH₃, Z═H and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 5, 81.3 mg (0.32 mmol) ofN-phthaloyl-O-quinolin-3-ylmethyl-hydroxylamine was reacted with 12 mg(0.24 mmol) of hydrazine hydrate. Then 7 μl of glacial acetic acid wasadded followed by 27 mg (0.04 mmol) of the compound of Example 3. Afterisolation, 24 mg of the desired product were obtained.

MS (ESI) m/z 846.98 (M+H)⁺.

Example 8

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O—CH₂—(2-quinolyl), X and Y TakenTogether with the Carbon Atom to Which They are Attached are C═N—Ac,L═CH₂CH₃, Z═H and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 5, 81.3 mg (0.32 mmol) ofN-phthaloyl-O-quinolin-2-ylmethyl-hydroxylamine was reacted with 12 mg(0.24 mmol) of hydrazine hydrate. Then 7 μl of glacial acetic acid wasadded followed by 27 mg (0.04 mmol) of the compound of Example 3. Afterisolation, 24 mg of the desired product were obtained.

MS (ESI) m/z 846.96 (M+H)⁺.

Example 9

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O-5-pyridin-2-ylthiophen-2yl-methyl, Xand Y Taken Together with the Carbon Atom to Which They are Attached areC═N—Ac, L═CH₂CH₃, Z═H and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 4, 27 mg (0.04 mmol) of the compound of Example 3,17 mg (0.08 mmol) ofO-(5-pyridin-2-yl-thiophen-2-ylmethyl)-hydroxylamine and 2.3 μl (0.04mmol) of glacial acetic acid were combined in 2 ml of ethanol. Afterisolation, 22 mg of the desired product were obtained.

MS (ESI) m/z 774.48 (M+H)⁺.

Example 10

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O-3-pyrimidin-2-ylprop-2-ynyl, X and YTaken Together with the Carbon Atom to Which They are Attached areC═N—Ac, L═CH₂CH₃, Z═H and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 4, 30 mg (0.04 mmol) of the compound of Example 3,20 mg (0.1 mmol) of O-(3-pyrimidin-2-yl-prop-2-ynyl)-hydroxylamine and2.3 μl (0.12 mmol) of triethyl amine were combined in 5 ml of ethanol.After isolation, 23 mg of the desired product were obtained.

MS (ESI) m/z 800.44 (M+H)⁺.

Example 11

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O-Ph, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H andR₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 5, 81.3 mg (0.32 mmol) ofN-phthaloyl-O-phenyl-hydroxylamine were reacted with 12 mg (0.24 mmol)of hydrazine hydrate. Then 7 μl of glacial acetic acid was addedfollowed by 27 mg (0.04 mmol) of the compound of Example 4. Afterisolation, 24 mg of the desired product were obtained.

MS (ESI) m/z 760.12 (M+H)⁺.

Example 12

Compound of Formula I: A═NHCH₂Ph, B═H, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H andR₂′═H

To a solution of the compound of Example 3 (34 mg, 0.05 mmol), aceticacid (5.7 μl, 0.1 mmol) and benzyl amine (16.4 μl, 0.15 mmol) in 3 ml ofmethanol was added NaCNBH₄(6.6 mg, 0.1 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 5 hours andquenched with 5% Trisamine, extracted with ethyl acetate (15 ml), washedwith brine (15 ml), and dried over Na₂SO₄. The solvent was removed undervacuum and the residue was purified by flash chromatography (SiO₂,CH₂Cl₂:2M ammonia in methanol=95:5) to give the title compound (25 mg)

MS (ESI) m/z 760.26 (M+H)⁺.

Example 13

Compound of Formula I: A═NHCH₂CH₂Ph, B═H, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H andR₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 12, 53.5 mg (0.08 mmol) of the compound of Example3, 30 g (0.24 mmol) of phenethyl amine, 9.2 μl of glacial acetic acidand 10 mg (0.16 mmol) of sodium cyanoborohydride were combined in 5 mlof methanol. After isolation, 40 mg of the desired product wereobtained.

MS (ESI) m/z 774.25 (M+H)⁺.

Example 14

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH₂, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═N—O—CH₂—O—CH₃, L═CH₂CH₃,Z═H, and R₂′═Ac

Step 14a: Compound of Formula 1-5: V═N—O—H, R₁₁═H and R₂′═Ac

To a solution of the compound from Step 1b (4.2 g, 4.5 mmol) in 50 mlmethanol was added 2M HCl (10 ml). The mixture was refluxed for 1.5hours, condensed to 30 ml, diluted with saturated NaHCO₃(30 ml),extracted with ethyl acetate (50 ml) and dried over Na₂SO₄. The solventwas evaporated and the residue was purified by silia gel chromatography(hexane:acetone/1:1) to give the title compound (2.5 g).

MS (ESI) m/z 685 (M+H)⁺. ¹³C-NMR (100 MHz, CDCl₃): δ 175.2, 170.2,166.3, 143.6, 119.3, 99.6, 82.2, 79.5, 78.1, 77.5, 76.0, 73.7, 71.7,68.9, 65.5, 63.3, 43.8, 40.8, 37.4, 35.9, 34.3, 31.1, 25.6, 23.3, 21.7,21.3, 19.9, 19.6, 17.1, 15.7, 14.7, 11.9, 7.9.

Step 14b: Compound of Formula 1-5: V═N—O—CH₂OCH₃, R₁₁═H and R₂′═Ac

To a solution of the compound from Step 14a (6.85 g, 10 mmol) in 40 mlDMF was added NaH (303 mg, 1.3 mmol) at 0° C., portion by portion. After10 minutes, MOM-Cl (900 ul, 1.15 mmol) was added at 0° C. during 15minutes. The mixture was stirred at room temperature for 16 hours andquenched with saturated NaHCO₃ (60 ml), extracted with ethyl acetate (60ml) and dried over Na₂SO₄. The solvent was evaporated and the residuewas purified by silica gel chromatography (hexane:acetone/1:1) to givethe title compound (4.5 g)

MS (ESI) m/z 729 (M+H)⁺.

Step 14c. Compound of Formula I: A and B Taken with Together with theCarbon Atom to Which They are Attached are C═CH₂, X and Y Taken Togetherwith the Carbon Atom to Which They are Attached are C═N—O—CH₂—O—CH₃,L═CH₂CH₃, Z═H, and R₂′═Ac

To a solution of the compound from Step 14b (4.4 g, 6 mmol) in 50 mldichloromethane was added a solution of Dess-Martin reagent (3.05 g, 7.2mmol) in 20 ml of dichloromethane. The mixture was stirred at roomtemperature for 2 hours. The reaction was quenched by addition ofsaturated NaHCO₃(50 ml) and Na₂S₂O₃ (10.4 g, 42 mmol). The organic layerwas separated and dried over Na₂SO₄. The solvent was removed and theresidue was purified by flash chromatography (SiO₂, hexane:acetone/1:1)to give the title compound (3.0 g)

MS (ESI) m/z 727.32 (M+H)⁺¹³C NMR(CDCl₃): δ 205.8, 169.8, 168.3, 168.1,142.0, 123.5, 100.9, 98.4, 79.1, 78.5, 76.0, 73.4, 71.7, 69.1, 65.5,63.5, 56.5, 50.8, 46.5, 40.7, 37.8, 34.4, 30.8, 26.9, 23.4, 21.5, 21.2,20.1, 19.3, 17.4, 15.0, 14.0, 13.9, 12.5.

Example 15

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH₂, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═N—O—CH₂—O—CH₃, L═CH₂CH₃,Z═H and R₂′═H

A solution of the compound of Example 14 (440 mg, 0.6 mmol) in 5 mlmethanol was refluxed for 4 hours and concentrated to give the desiredcompound without purification.

MS (ESI) m/z 685.18 (M+H)⁺

Example 16

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═O, X and Y Taken Together with the CarbonAtom to Which They are Attached are C═N—O—CH₂—O—CH₃, L═CH₂CH₃, Z═H andR₂′═H

A solution of the compound of Example 15 (420 mg, 0.6 mmol) in 7 mlmethanol and 20 ml CH₂Cl₂ was purged with 03 at −78° C. until thesolution became light blue. Nitrogen was bubbled through the solution toremove excess 03 and then PPh₃ (2 eq) was added. The mixture was warmedto room temperature and stirred at room temperature for 2 hours,concentrated and the residue dissolved in 10 ml THF and another 2 eq. ofPPh₃ was added. The resulting mixture was refluxed overnight andconcentrated. The residue was purified by flash chromatography (SiO₂,CH₂Cl₂:2M ammonia in CH₃OH=95:5) to give the title compound (280 mg).

MS (ESI) m/z 687.25 (M+H)⁺¹³C NMR(CDCl₃): δ 205.8, 205.8, 170.2, 166.7,102.4, 98.8, 80.6, 80.5, 78.8, 76.7, 76.0, 75.6, 70.5, 69.7, 69.5, 66.1,60.6, 57.1, 50.8, 45.8, 40.5, 38.2, 34.3, 28.6, 26.9, 23.1, 21.5, 21.3,19.9, 19.4, 17.0, 15.4, 14.5, 14.4, 13.0, 11.7.

Example 17

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═NOCH₂ Ph, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═N—O—CH₂—O—CH₃, L═CH₂CH₃,Z═H and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 4, 87 mg (0.13 mmol) of the compound of Example 16,41.5 mg (0.26 mmol) of O-benzyl hydroxylamine and 21 μl (0.26 mmol) ofpyridine were combined in 10 ml of ethanol. After isolation, 75 mg ofthe desired product was obtained.

ESMS: 774.35 (M+H)⁺

Example 18

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═O, X and Y Taken Together with the CarbonAtom to Which They are Attached are C═O, L═CH₂CH₃, Z═H, and R₂′═Ac

Step 18a. Compound of Formula 3-1: R₁₁═H, R₁₃═H and R_(p)=Tert-butylDimethyl Silyl

To a suspension of NaH (1.26 g, 50 mmol) in 40 ml of THF was added asolution of 2-methylene-1,3-propane diol (4.4 g, 50 mmol) in 30 ml ofTHF. The mixture was stirred at room temperature for 45 minutes and thena solution of tert-butyl dimethylsilyl chloride (7.54 g, 50 mmol) in 30ml of THF added. The mixture was stirred at room temperature for 1 hourand then quenched with saturated NaHCO₃ (200 ml), extracted withdiethylether (150 ml×2) and the combined organic layers were dried overMgSO₄. The solvent was removed and the resulting oil was purified byflash chromatography (SiO₂, hexane:ethyl acetate/10:1) to give the titlecompound (8.4 g).

Step 18b: Compound of Formula 3-1: R₁₁═H, R₁₃=t-butoxycarbonyl andR_(p)=Tert-butyl Dimethyl Silyl

To a solution of the compound from Step 18a (81 g, 40 mmol) in 100 ml ofmethylenechloride was added di-tertbutyl dicarbonate (13.1 g, 60 mmol),tetrabutylammoniahydrogensulfate (1.2 g, 3.5 mmol) and 30 ml of 6N NaOH.The mixture was stirred at room temperature for 16 hours, diluted with100 ml of methylene chloride and washed with saturated NaHCO₃ (200ml×3). The organic layer was dried over Na₂SO₄ and the solvent wasremoved under vacuum. The residue was purified by flash chromatography(SiO₂, hexane:ethylacetate/96:4) to give the title compound (6.8 g).

Step 18c. Compound of Formula 3-2: R_(p)=Tert-butyl Dimethyl Silyl,R_(6══Ac, R) ₁₁═H, R₂′═Ac and R₄″═Ac

To a solution of erythromycin A oxime 9,2′,4″-triacetate from Step 1a(22 g, 25 mmol), the compound from Step 18b (9.1 g, 30 mmol) and dppb(853 mg, 1 mmol) in 250 ml THF was added Pd₂(dba)₃ (916 mg, 1 mmol). Themixture was refluxed overnight, concentrated and purified by flashchromatography (SiO₂, acetone:hexane/1:3) to give the title compound (25g).

MS (ESI) m/z 1059.65 (M+H)⁺¹³C NMR(CDCl₃): δ 181.2, 179.3, 175.9, 175.5,173.5, 148.5, 116.5, 104.8, 102.0, 85.2, 84.3, 83.9, 83.6, 82.8, 82.2,79.7, 78.1, 77.6, 75.6, 72.4, 70.4, 69.0, 68.6, 54.6, 49.9, 46.2, 43.2,40.8, 36.5, 33.6, 31.4, 27.1, 27.0, 26.6, 26.3, 25.2, 25.1, 24.0, 23.7,22.0, 20.4, 16.0, 15.2, 0.5, 0.0.

Step 18d: Compound of Formula (3-2) Rp=Tert-butyl Dimethyl Silyl, R₆═H,R₁₁═H, R₂′═H, R₄″═Ac

A solution of the compound of Step 18c (3.18 g, 3 mmol) in 80 mlmethanol was refluxed for 8 hours. The solution was concentrated andpurified by flash chromatography (SiO₂, 2M ammonia inmethanol:dichloromethane/3:97) to give the title compound (2.6 g, 89%).

MS (ESI) m/z 975.47 (M+H)⁺¹³C NMR(CDCl₃): δ 179.5, 178.9, 175.7, 150.6,121.5, 106.8, 101.4, 85.3, 83.9, 83.7, 82.4, 82.0, 79.3, 77.8, 76.7,76.5, 72.7, 70.4, 70.1, 69.3, 68.3, 54.6, 49.8, 45.5, 43.0, 42.9, 40.6,38.1, 34.0, 31.1, 30.5, 27.1, 26.3, 26.1, 26.0, 24.3, 23.7, 23.5, 21.5,19.9, 15.7, 14.8, 0.5, 0.0.

Step 18e. Compound of Formula 3-4: R_(p)═H, R₁₁═H, R₂′═H and R₄″═Ac

To an emulsion of the compound of Step 18d (2.44 g, 2.5 mmol) in 25 mlof isopropanol and 30 ml of water was added formic acid (380 μl, 10mmol) and Na₂S₂O₄ (1.39, 8 mmol). The reaction mixture was heated to 90°C. and stirred for 8 hours. The solution was diluted with ethyl acetate(60 ml) and washed with saturated NaHCO₃ (60 ml×3). The organic layerwas separated and dried over anhydrous Na₂SO₄(˜5 g), concentrated andpurified by flash chromatography (SiO₂, 2M ammonia inmethanol:dichloromethane/3:97) to give the title compound (1.7 g).

MS (ESI) m/z 846.54 (M+H)⁺. ¹³C NMR(CDCl₃): δ 221.3, 175.3, 170.6,147.0, 114.1, 101.8, 96.6, 79.9, 79.2, 78.8, 78.7, 77.4, 75.0, 72.8,71.4, 68.8, 67.8, 65.4, 65.3, 63.7, 63.4, 60.6, 49.6, 45.5, 44.8, 40.4,38.2, 38.0, 35.6, 22.0, 21.2, 21.1, 19.6, 18.6, 16.5, 14.4, 12.2, 10.6,9.8.

Step 18f. Compound of Formula 3-4: R_(p)═H, R₁₁═H, R₂′═Ac and R₄″═Ac

Acetic anhydride (94 ul, 1 mmol) was added to a solution of the compoundof Step 18e (338.4 mg, 0.4 mmol) in dichloromethane (5 ml). The mixturewas stirred at room temperature for 16 hours. Solvent was removed undervacuum and the product was purified by flash chromatography (SiO₂,acetone:hexane/4:6 vl) to give the title compound (330 mg).

MS (ESI) m/z 888.58 (M+H)⁺¹³C NMR(CDCl₃): δ 221.3, 175.1, 170.6, 170.3,146.8, 114.2, 99.6, 96.5, 79.9, 79.1, 78.5, 78.4, 77.1, 74.9, 72.8,72.1, 68.9, 67.1, 65.1, 63.7, 63.5, 63.1, 49.3, 45.5, 44.8, 40.6, 38.0,37.7, 37.6, 35.5, 29.4, 21.8, 21.3, 21.1, 21.0, 19.4, 18.6, 16.6, 12.2,10.6, 9.6.

Step 18g. Compound of Formula 3-4: R_(p)=Tert-butoxycarbonyl, R₁₁═H,R₂′═Ac and R₄″═Ac

Di-tert-butyl-dicarbonate (69 μl, 0.3 mmol) was added to a solution ofthe compound of Step 18f (178 mg, 0.2 mmol) and triethylamine (56 μl,0.4 mmol) in dichloromethane (8 ml) at room temperature. After 10minutes, DMAP (12.2 mg, 0.1 mmol) was added. The resulting solution wasstirred at room temperature for 2 hours. Solvent was removed undervacuum and the product was purified by flash chromatography (SiO₂,acetone:hexane/1:3 vl) to give the title compound (180 mg).

MS (ESI) m/z 988.41 (M+H)⁺¹³C NMR(CDCl₃): δ 219.6, 174.6, 170.6, 170.3,153.8, 141.3, 116.8, 99.6, 96.5, 82.0, 80.2, 79.4, 78.7, 78.6, 76.8,74.9, 72.9, 72.4, 69.1, 67.9, 67.2, 64.8, 63.6, 63.4, 49.4, 45.2, 44.8,41.0, 37.9, 37.7, 37.6, 35.6, 31.8, 31.3, 31.2, 28.2, 28.1, 22.9, 21.8,21.5, 21.4, 21.1, 19.4, 18.7, 16.7, 16.6, 14.4, 12.5, 10.7, 9.7

Step 18h. Compound of Formula 3-6: R₁₁═H, R₂′═Ac and R₄″═Ac

1,4-Bis(diphenylphosphino)butane (8.5 mg, 0.02 mmol) and Pd₂(dba)₃ (9.2mg, 0.01 mmol) were added to a solution of the compound of Step 18g(98.8 mg, 0.1 mmol) in 2 ml anhydrous THF at room temperature. Theresulting mixture was refluxed for 30 minutes. Solvent was removed undervacuum to give the title compound (85 mg).

MS (ESI) m/z 870.49 (M+H)⁺

Step 18i. Compound of Formula 1-5: V═O, R₁₁═H and R₂′═Ac

To a solution of the compound of Step 18h (700 mg, 0.8 mmol) in 10 mlethanol was added 25 ml of 1M HCl. The mixture was refluxed for 2 hoursand then cooled to room temperature. The pH of the mixture was adjustedto 10 by addition of 2M NaOH and then extracted with ethyl acetate. Theextract was dried over Na₂SO₄, concentrated and the residue purified byflash chromatography (SiO₂, hexane:acetone/1:1) to give the titlecompound (480 mg).

MS (ESI) m/z 670.23 (M+H)⁺¹³C NMR(CDCl₃): δ 216.3, 175.0, 170.1, 141.8,122.1, 99.4, 81.1, 79.0, 77.7, 77.5, 76.2, 75.6, 72.1, 71.7, 68.8, 65.6,63.2, 60.5, 46.5, 43.7, 40.8, 39.1, 38.6, 35.9, 31.1, 23.0, 21.6, 21.3,21.2, 19.8, 18.5, 17.3, 14.8, 14.3, 13.0, 11.7, 7.9.

Step 18j. Compound of Formula I: A and B Taken Together with the CarbonAtom to Which They are Attached are C═O, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═O, L═CH₂CH₃, Z═H and R₂′═Ac

To a solution of the compound of Step 18i (480 mg, 0.7 mmol) in 10 ml ofdichloromethane was added Dess-Martin reagent (385 mg, 0.9 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 2hours and quenched with saturated NaHCO₃ (15 ml) and sodium thiosulfate(0.4 g). The organic phase was separated, washed with brine (15 ml),dried over Na₂SO₄ and concentrated. The residue was purified by flashchromatography (SiO₂, hexanes:acetone/2:1) to give the title compound(400 mg).

MS (ESI) m/z 668.02 (M+H)⁺¹³C NMR(CDCl₃): δ 218.2, 205.8, 170.0, 168.1,140.9, 125.1, 101.0, 78.9, 78.3, 76.5, 75.0, 72.7, 70.4, 69.3, 65.7,63.6, 50.8, 46.6, 46.3, 40.9, 39.3, 39.1, 30.8, 23.4, 21.6, 21.3, 19.9,18.5, 17.8, 14.2, 14.0, 12.5, 12.4.

Example 19

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH₂, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═O, L═CH₂CH₃, Z=1H and R₂′═H

A solution of the compound of Example 18 (300 mg, 0.45 mmol) in 10 ml ofmethanol was refluxed for 8 hours. Solvent was removed under vacuum andthe residue was purified by silica gel chromatography (CH₂Cl₂:2M ammoniain methanol/97:3 vl) to give the title compound (270 mg).

MS (ESI) m/z 626.10 (M+H)⁺. ¹³C NMR(CDCl₃): δ 218.4, 205.9, 168.1,141.0, 125.2, 103.5, 78.7, 78.3, 76.6, 76.1, 72.6, 70.6, 70.3, 69.8,66.1, 65.7, 50.9, 47.3, 46.4, 40.5, 39.4, 39.3, 28.5, 23.4, 21.5, 20.0,18.5, 17.9, 14.6, 14.1, 12.5, 12.4.

Example 20

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═O, X and Y Taken Together with the CarbonAtom to Which They are Attached are C═O, L═CH₂CH₃, Z═H, and R₂′═H

A solution of the compound of Example 19 (94 mg, 0.15 mmol) in 2 ml ofmethanol and 4 ml of CH₂Cl₂ was purged with 03 at −78° C. until thesolution became light blue. Nitrogen was bubbled through the solution toremove excess 03 and then PPh₃ (2 eq) was added. The mixture was warmedto room temperature and stirred at room temperature for 2 hours. Themixture was concentrated and the residue was dissolved in 5 ml of THFand another 2 eq of PPh₃ was added. The resulting mixture was refluxedovernight and concentrated. The residue was purified by flashchromatography (SiO₂, CH₂Cl₂:2M ammonia in methanol/95:5) to give thetitle compound (80 mg).

MS (ESI) m/z 628.10 (M+H)⁺¹³C-NMR(CDCl₃): δ 215.2, 205.6, 205.3, 169.9,102.5, 80.5, 79.4, 78.6, 77.5, 76.3, 76.1, 75.3, 70.5, 69.8, 68.5, 66.1,51.0, 46.3, 46.2, 40.5, 39.8, 39.0, 28.5, 22.9, 21.5, 19.8, 18.3, 17.3,14.4, 13.6, 12.4, 11.6

Example 21

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O—CH₂Ph, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═O, L═CH₂CH₃, Z═H, and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 4, 19 mg (0.03 mmol) of the compound of Example 20,10 mg (0.06 mmol) of O-benzyl hydroxylamine and 5 μl (6 mmol) ofpyridine were combined in 5 ml of ethanol. After isolation, 20 mg of thedesired product was obtained.

MS (ESI) m/z 733.24 (M+H)⁺

Example 22

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH₂, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═NH, L═CH₂CH₃, Z═H, andR₂′═H

Potassium carbonate (50 mg) was added to a solution of the compound ofExample 2 in methanol (6 ml). The mixture was stirred at roomtemperature for 3 days. The solvent was removed in vacuo and the residuewas purified by flash chromatography (SiO₂, CH₂Cl₂:2M ammonia inmethanol/95:5) to give the title compound (70 mg).

MS (ESI) m/z: 625.36(M+H)⁺

Example 23

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O—CH₂-p-NO₂Ph, X and Y Taken Togetherwith the Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃,Z═H, and R₂′═H

A solution of the compound of Example 3 (53.5 mg, 0.08 mmol), benzylhydroxylamine HCl salt (33 mg, 0.16 mmol) and pyridine (0.16 mmol) in 4ml ethanol was stirred at room temperature for 1 hour. The solvent wasremoved in vacuo and the residue was purified by flash chromatography(SiO₂, CH₂Cl₂:2M ammonia in methanol/95:5) to give the title compound(52 mg) as a 3:1 mixture of cis and trans.

MS (ESI) m/z: 819.22(M+H)⁺

Example 24

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O—(CH₂)₂-Ph, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H,and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 5, 50 mg (0.074 mmol) of the compound of Example 3,and 100 mg (0.37 mmol) of N-phthaloyl-O-phenethyl-hydroxylamine werereacted to give the title compound.

MS (ESI) m/z: 788(M+H)⁺

Example 25

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O—(CH₂)₃-Ph, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H,and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 5, 50 mg (0.074 mmol) of the compound of Example 3,and 105 mg (0.37 mmol) of N-phthaloyl-0-1-(3-phenyl)propyl-hydroxylaminewere reacted to give the title compound.

MS (ESI) m/z: 802(M+H)⁺

Example 26

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═N—O—CH₂—CH═CH-Ph, X and Y Taken Togetherwith the Carbon Atom to Which They are attached are C═N—Ac, L═CH₂CH₃,Z═H, and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 5, 50 mg (0.074 mmol) of the compound of Example 3,and 105 mg (0.37 mmol) ofN-phthaloyl-O-1-(3-phenyl)prop-2-enyl-hydroxylamine were reacted to givethe title compound.

MS (ESI) m/z: 800(M+H)⁺

Example 27

Compound of Formula I: A is NH—(CH₂)₃-Ph, B is H, X and Y Taken Togetherwith the Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃,Z═H, and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 12, 33.5 mg (0.05 mmol) of the compound of Example3, and 21.8 μl (0.1 mmol) of 3-phenyl propylamine were reacted to give18 mg of the title compound.

MS (ESI) m/z: 788(M+H)⁺

Example 28

Compound of Formula I: A is NH—(CH₂)₃-Ph, B is H, X and Y Taken Togetherwith the Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃,Z═H, and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 12, 24 mg (0.05 mmol) of the compound of Example 3,and 33.5 μL (0.15 mmol) of 4-phenyl butylamine were reacted to give 12mg of the title compound.

MS (ESI) m/z: 802(M+H)⁺

Example 29

Compound of Formula I: A is CH₂—CH═CH₂, B is OH, X and Y Taken Togetherwith the Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃,Z═H, and R₂′═H

A solution of the compound of Example 3 (0.23 g, 0.34 mmol) in 20 mLanhydrous THF was cooled to −78° C. Allylmagnesium bromide in THF (1.0M, 1.5 mL, 1.5 mmol) was added via syringe. The reaction mixture wasstirred for 1 hour at −78° C. and then was quenched with aqueous NaHCO₃.The mixture was warmed to room temperature slowly and then extractedwith CH₂Cl₂ (3×30 mL). The combined organic layers were dried overanhydrous Na₂SO₄. The solvent was evaporated and the residue waspurified by flash chromatography (SiO₂, CH₂Cl₂ containing 5% 2M ammoniasolution in methanol) to provide the title compound (0.21 g, 86%).

MS (ESI) m/z 711 (M+H)⁺¹³C-NMR (100 MHz, CDCl₃): δ 205.5, 186.1, 179.9,169.7, 132.9, 118.3, 102.3, 80.0, 79.4, 76.1, 73.7, 72.7, 70.4, 70.4,69.7, 66.2, 50.8, 44.9, 41.2, 40.5, 39.8, 39.4, 37.1, 28.6, 25.5, 23.6,21.5, 20.2, 20.0, 17.3, 15.9, 14.3, 12.6, 12.0.

Example 30

Compound of Formula I: A═CH₂-Ph, B is OH, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H,and R₂′═H

The compound of Example 3 (70 mg, 0.1 mmol) was treated withbenzylmagnesium bromide (0.85 M in THF, 0.6 μL, 0.5 mmol) as describedin Example 29. After the same work up, the crude mixture was purified byflash chromatography (SiO₂, CH₂Cl₂ containing 5% 2M ammonia solution inmethanol) to provide the title compound (12 mg, 18%).

MS (ESI) m/z 761 (M+H)⁺¹³C-NMR (100 MHz, CDCl₃): δ 205.7, 186.3, 179.5,169.8, 136.3, 131.0, 128.1, 126.5, 101.8, 80.1, 79.3, 76.0, 73.5, 73.1,70.6, 70.1, 69.2, 66.6, 50.9, 44.8, 42.4, 40.5, 39.8, 39.3, 37.1, 29.9,25.6, 23.6, 21.3, 20.2, 20.1, 17.3, 15.9, 14.4, 12.7, 12.0.

Example 31

Compound of Formula I: A═(CH₂)₂-Ph, B═OH, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H,and R₂′═H

The compound of Example 3 (70 mg, 0.1 mmol) was treated withphenethylmagnesium bromide (1.0 M in THF, 0.5 mL, 0.5 mmol) as describedin Example 29. After the same work up, the crude mixture was purified byflash chromatography (SiO₂, CH₂Cl₂ containing 5% 2M ammonia solution inmethanol) to provide the title compound (12 mg, 16%).

MS (ESI) m/z 775 (M+H)⁺

Example 32

Compound of Formula I: A═Ph, B═OH, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H, andR_(2′)═H

The compound of Example 3 (70 mg, 0.1 mmol) was treated withphenylmagnesium bromide (1.0 M in THF, 0.5 mL, 0.5 mmol) as described inExample 29. After the same work up, the crude mixture was purified byflash chromatography (SiO₂, CH₂Cl₂ containing 5% 2M ammonia solution inmethanol) followed by a semi-prep. HPLC to provide the title compound (5mg).

MS (ESI) m/z 747 (M+H)⁺

Example 33

Compound of Formula I: A is CH₂—CH═CH-Ph, B is OH, X and Y TakenTogether with the Carbon Atom to Which They are Attached are C═N—Ac,L═CH)CH₃, Z═H, and R₂′═H

The compound from Example 29 (50 mg, 0.07 mmol), iodobenzene (32 mg,0.15 mmol), Pd(OAc)₂ (2.5 mg), (o-Tolyl)₃P (10 mg) and triethyl amine(0.1 mL, excess) were dissolved in 3 ml CH₃CN and the solution wasdegassed at −40° C. The reaction mixture was warmed to room temperatureunder nitrogen, heated at 50° C. for 1 hour, and then left at 80° C. for12 hours. The reaction mixture was diluted with ethyl acetate, washedwith saturated aqueous NaHCO₃, and dried over anhydrous Na₂SO₄. Thesolvent was evaporated and the residue was purified by flashchromatography (SiO₂, CH₂Cl₂ containing 5% 2M ammonia solution inmethanol) to provide the title compound (40 mg, 76%).

MS (ESI) m/z 787 (M+H)⁺

Selected ¹³C-NMR (100 MHz, CDCl₃): δ 205.5, 186.3, 179.7, 169.9, 137.7,133.2, 128.6, 127.2, 126.5, 124.8, 101.9, 80.0, 79.4, 76.1, 73.9, 73.2,70.5, 70.1, 69.3, 66.3, 50.9, 46.5, 44.8, 40.7, 40.2, 39.8, 39.4, 37.0,29.4, 25.6, 23.6, 21.3, 20.2, 20.1, 17.3, 16.0, 14.5, 12.6, 11.9, 8.9.

Example 34

Compound of Formula I: A is (CH₁₂)₃-Ph, B is OH, X and Y Taken Togetherwith the Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃,Z═H, and R₂′═H

The compound from Example 24 (15 mg, 0.02 mmol) was hydrogenated under 1atm H₂ over Pd-C in ethanol at room temperature for 24 hours. Thesolvent was evaporated under vacuum. Purification by flashchromatography (SiO₂, CH₂Cl₂ containing 5% 2M ammonia solution inmethanol) gave the title compound (13.2 mg, 88%).

MS (EST) m/z 789 (M+H)⁺

Example 35

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH—CH═CH-Ph, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H,and R₂′═H

Step 35a: Compound of Formula (1-5): V is N—Ac, R₁₁ is CH—CH-Ph, R₂′═Ac

To a solution of the compound of formula (1-5), wherein V═N—Ac, R₁₁═H,and R₂′═Ac (0.5 g, 0.7 mmol) in 8 ml anhydrous DMF, β-bromostyrene (0.15ml, 1.2 mmol) and K₂CO₃ (200 mg, 1.5 mmol) were added at roomtemperature. The mixture was degassed briefly and a catalytic amount ofdihydrogen dichlorobis(di-tert-butylphosphinito-κP)palladate(II) (POPdfrom Combiphos catalysts, Inc.) was added. The reaction mixture washeated to 100° C. in a sealed tube for 48 hours. Ethyl acetate (50 mL)was added and the solution was washed 3 times with aqueous NaHCO₃. Theorganic layer was dried over anhydrous Na₂SO₄. The solvent wasevaporated under vacuum and the residue was purified by flashchromatography (SiO₂, acetone:hexanes/1:1) to provide the titlecompound.

MS (ESI) m/z 813 (M+H)⁺

Step 35b: Compound of Formula I: A and B Taken Together with the CarbonAtom to Which They are Attached are C═CH—CH═CH-Ph, X and Y TakenTogether with the Carbon Atom to Which They are Attached are C═N—Ac,L═CH₂CH₃, Z═H, and R₂′═Ac

The compound from Step 35a was dissolved in CH₂Cl₂ and Dess-Martinperiodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one)(0.3 g, 0.7 mmol) was added. The mixture was stirred for 1 hour and thenaqueous NaHCO₃ was added. The mixture was extracted 3 times with CH₂Cl₂and the combined organic layers were dried over anhydrous Na₂SO₄. Thesolvent was evaporated under vacuum and the residue was purified byflash chromatography (SiO₂, acetone:hexanes/2:3) to provide the titlecompound (0.24 g, 42%).

MS (ESI) m/z 811 (M+H)⁺

Step 35c: Compound of Formula I: A and B Taken Together with the CarbonAtom to Which They are Attached are C═CH—CH═CH-Ph, X and Y TakenTogether with the Carbon Atom to Which They are Attached are C═N—Ac,L═CH₂CH₃, Z═H, and R₂′═H

A solution of the compound from Step 35b (0.16 g, 0.05 mmol) in 10 mL ofmethanol was stirred for 48 hours at room temperature. The solvent wasevaporated under vacuum. Purification by flash chromatography (SiO₂,CH₂Cl₂ containing 3% 2M ammonia solution in methanol) gave the titlecompound (0.12 g, 79%).

MS (ESI) m/z 769 (M+H)⁺¹³C-NMR (100 MHz, CDCl₃): δ 206.4, 184.7, 177.9,167.8, 137.6, 136.4, 136.2, 134.2, 128.7, 128.0, 127.0, 124.0, 103.4,79.8, 76.4, 72.5, 70.5, 69.7, 66.8, 66.6, 66.2, 51.1, 47.2, 40.5, 38.8,28.6, 25.4, 23.9, 21.5, 20.0, 17.7, 15.2, 14.1, 13.1.

Example 36

Compound of Formula I: A is (CH₂)₃-Ph, B is H, X and Y Taken Togetherwith the Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃,Z═H, and R₂′═H

The compound of Example 35 (15 mg, 0.02 mmol) was hydrogenated under H₂(30 psi) over Pd-C in ethanol at room temperature for 12 hours. Thesolvent was evaporated under vacuum. Purification by flashchromatography (SiO₂, CH₂Cl₂ containing 5% 2M ammonia solution inmethanol) gave the title compound (7.0 mg, 50%).

MS (ESI) m/z 773 (M+H)⁺

Example 37

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH—CH═CH-3-pyridyl, X and Y Taken Togetherwith the Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃,Z═H, and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 35, 190 mg (0.2 mmol) of the compound of Example 1,and 35 mg (0.2 mmol) of 1-bromo-2-(3-pyridyl)ethylene were reacted togive the title compound.

MS (ESI) m/z 770 (M+H)⁺

Example 38

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH—CH═CH-3-quinolyl, X and Y TakenTogether with the Carbon Atom to Which They are Attached are C═N—Ac,L═CH₂CH₃, Z═H, and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 35, 240 mg (0.35 mmol) of the compound of Example 1,and 100 mg (0.43 mmol) of 1-bromo-2-(3-quinolyl)ethylene were reacted togive the title compound.

MS (ESI) m/z 794 (M+H)⁺

Example 39

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH-2-quinolyl, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H,and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 35, 500 mg (0.7 mmol) of the compound of Example 1,and 25 mg (1.2 mmol) of 3-bromoquinoline were reacted to give the titlecompound.

MS (ESI) m/z 820 (M+H)⁺

Example 40

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH-2-quinolyl, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—H, L═CH₂CH₃, Z═H, andR₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 35, 63 mg (0.1 mmol) of the compound of Example 22,and 42 mg (0.2 mmol) of 3-bromoquinoline were reacted to give 7.5 mg ofthe title compound.

MS (ESI) m/z 742 (M+H)⁺

Example 41

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH-4-biphenyl, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H,and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 35, 213 mg (0.3 mmol) of the compound of Example 1,and 142 mg (0.6 mmol) of 4-bromobiphenyl were reacted to give the titlecompound.

MS (ESI) m/z 819 (M+H)⁺

Example 42

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH-3-biphenyl, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H,and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 35, 213 mg (0.3 mmol) of the compound of Example 1,and 103 μL (0.6 mmol) of 3-bromobiphenyl were reacted to give the titlecompound.

MS (ESI) m/z 819 (M+H)⁺

Example 43

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH-4-phenoxyphenyl, X and Y Taken Togetherwith the Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃,Z═H, and R₂′═H

Using essentially the same procedure as for the preparation of thecompound of Example 35, 142 mg (0.2 mmol) of the compound of Example 1,and 71 μL (0.4 mmol) of 4-bromodiphenyl ether were reacted to give thetitle compound.

MS (ESI) m/z 835 (M+H)⁺

Example 44

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH-Ph, X and Y Taken Together with theCarbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H, andR₂′═H

Step 44a: 3-propanone-1,3-di-t-butyldicarbonate

To a solution of 1,3-dihydroxyacetone dimer (36.03 g, 0.20 mol) and DMAP(1.22 g, 10.0 mmol) in dichloromethane (80 mL) and pyridine (97.0 mL,1.20 mol) was added a solution of di-tert-butyl dicarbonate (200.0 g,0.92 mol) in dichloromethane (40 mL) via a dropping funnel over 3 hoursat room temperature. After stirring at room temperature for 15 hours,the reaction mixture was condensed in vacuo. The residue was dilutedwith a 1:1 mixture of hexanes and diethyl ether, washed with saturatedaqueous CuSO₄, water and brine. The organic phase was dried over Na₂SO₄and the solvent was removed in vacuo. The residue was purified by flashchromatography (SiO₂, hexane:ethyl acetate gradient from 95:5 to 85:15)to give the title compound (45.0 g, 39%).

¹³C-NMR (125 MHz, CDCl₃): δ 198.5, 152.6, 83.5, 68.5, 27.6.

Step 44b: Compound of Formula 1-3: R₁₁═Ph and R₁₃=t-Bu

A suspension of benzyltriphenylphosphonium bromide (520 mg, 1.20 mmol)in THF (5.0 mL) was treated with n-butyl lithium (1.6 M in hexanes, 0.81mL, 1.30 mmol) at −78° C. under nitrogen. The mixture was warmed to −15°C. over 1 hour before a solution of the compound from Step 44a (290 mg,1.0 mmol) in THF (2.5 mL) was added at −70° C. The reaction mixture waswarmed to room temperature over 1 hour and stirred for a further 14hours at room temperature. The reaction mixture was diluted with ethylacetate and the organic phase was washed with water and brine, and driedover Na₂SO₄. The solvent was evaporated and the residue was purified byflash chromatography (SiO₂, hexanes:CH₂Cl₂/1:1) to give the titlecompound (253 mg, 70% yield).

¹³C-NMR (125 MHz, CDCl₃): δ 153.1, 153.0, 135.1, 134.6, 130.4, 128.6,128.2, 127.6, 82.0, 81.9, 68.4, 62.7, 27.6, 27.5.

Step 44c: Compound of Formula 1-4: R₆═Ac, R₁₁═Ph, R₂′═Ac, R₄″═Ac

A mixture of Erythromycin A oxime triacetate (525 mg, 0.60 mmol), thecompound from Step 44b (250 mg, 0.69 mmol),1,4-bis(diphenylphosphino)butane (51.2 mg, 0.12 mmol), andtris(dibenzylideneacetone)dipalladium (54.9 mg, 0.06 mmol) in THF (5.0mL) was degassed and heated to 75° C. for 15 hours. The solvent wasremoved under vacuum and the resulting residue was purified by flashchromatography (SiO₂, hexanes:acetone/4:11˜5:1) to give the titlecompounds as a 2.6:1 mixture of double bond isomers (330 mg, 55% yield).

MS (ESI) m/z: 1003 (M+H)⁺

Step 44d: Compound of Formula 1-4: R₆═Ac, R₁₁═Ph, R₂′═H, R₄″═Ac

The title compound was prepared by refluxing the compound from Step 44cin methanol according to the procedure described in Step 1 of Example 1.

MS (ESI) m/z: 919 (M+H)⁺

Step 44e: Compound of Formula 2-2: R₁₁═Ph, R₁₁′═H

A solution of the compound from Step 44d (0.30 mmol) in methanol (5.0mL) was treated with titanium (III) chloride (20% in 3% HCl, 0.77 mL)for 2 hours at room temperature, then for 1 hour at 50° C. The mixturewas then partitioned between CH₂Cl₂ and aqueous saturated NaHCO₃. Theaqueous solution was extracted with CH₂Cl₂ and the combined extractswere washed with brine and dried over Na₂SO₄. After evaporation, theresidue was purified by flash chromatography (SiO₂, CH₂Cl₂:2 M NH₃ inMeOH/98:2˜93:7) to give the title compounds as a 4:1 mixture of doublebond isomers (105 mg, 50% yield).

MS (ESI) m/z: 703 (M+H)⁺

Step 44f: Compound of Formula 1-5: V═N—Ac, R₁₁═Ph, R₂′═Ac

A solution of the compound from Step 44e (105 mg, 0.15 mmol) in CH₂Cl₂(3.0 mL) was treated with triethylamine (104 μL, 0.74 mmol) and aceticanhydride (42 μL, 0.45 mmol) at room temperature for 19 hours beforeevaporation and drying in vacuo to give the title compound.

MS (ESI) m/z 787 (M+H)⁺

Step 44 g: Compound of Formula I: A and B Taken Together with the CarbonAtom to Which They are Attached are C═CH-Ph, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H,and R₂′═Ac

A solution of the compound from Step 44f (0.15 mmol at most) in CH₂Cl₂(3.0 mL) was treated with Dess-Martin periodinane (108 mg, 0.25 mL) for4.5 hours at room temperature. The resulting mixture was partitionedbetween ethyl aceate and aqueous saturated NaHCO₃:Na₂S₂O₃/3:1. Theorganic phase was washed with water and brine. After drying (Na₂SO₄) andevaporation, the residue was purified by flash chromatography (SiO₂,hexanes:acetone/4:1˜1.5:1) to give the title compound as a 5:1 mixtureof double bond isomers (62.7 mg, 54% yield).

MS (ESI) m/z 785 (M+H)⁺

Step 44h: Compound of Formula I: A and B Taken Together with the CarbonAtom to Which They are Attached are C═CH-Ph, X and Y Taken Together withthe Carbon Atom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═H,and R₂′═H

A solution of the compound from Step 44g (62.7 mg, 0.08 mmol) inmethanol (3.0 mL) was stirred at room temperature for 5 days beforeevaporation. Purification by flash chromatography (SiO₂, CH₂Cl₂:2 M NH₃in MeOH/99:1˜96:4) gave the title compound as a 5:1 mixture of doublebond isomers (49.6 mg, 84%).

MS (ESI) m/z 743 (M+H)⁺

Example 45

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═CH-2-(2pyridyl)-thiophen-5-yl, X and YTaken Together with the Carbon Atom to Which They are Attached areC═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H

Step 45a: Compound of Formula 6-3: V is N—Ac, X_(A)═OH, X_(B)═H, R₂′═Ac

To a solution of the compound from Step 1f of Example 1 (8.70 g, 12.25mmol) in t-BuOH (18 mL) was added 4-methylmorpholine N-oxide (2.07 g,14.7 mmol) and OSO₄ (4% in water, 0.78 ml). The mixture was stirred atroom temperature for 1 hour and then partitioned between CH₂Cl₂ andaqueous saturated NaHCO₃. The aqueous layer was extracted with CH₂Cl₂and the combined organic extracts were dried over NaSO₄ and condensed invacuo. Purification by flash chromatography (SiO₂,hexanes:acetone/1:1˜1:3) afforded the title compound (6.90 g, 76% yield)as a 1:1 mixture of diastereoisomers.

MS (ESI) m/z 745 (M+H)⁺

Step 45b: Compound of Formula 6-2: V is N—Ac, X_(A)═OH, X_(B)═H, R₂′═Ac

A solution of the compound from Step 45a (2.00 g, 2.69 mmol) in acetoneand water (1:1, 20.0 mL) was treated with sodium periodate (1.15 g, 5.37mmol). The mixture was stirred at room temperature for 3.5 hours andthen partitioned between CH₂Cl₂ and aqueous saturated NaHCO₃. Theaqueous layer was extracted with CH₂Cl₂ and the combined organicextracts were dried over NaSO₄ and condensed in vacuo. Purification byflash chromatography (SiO₂, hexanes:acetone/1:1) afforded the titlecompound (1.50 g, 78% yield).

MS (ESI) m/z 713 (M+H)⁺¹³C NMR (CDCl₃): δ 205.4, 184.4, 175.8, 175.4,169.9, 99.2, 81.8, 80.6, 79.4, 78.2, 77.4, 76.5, 75.7, 71.4, 69.0, 68.8,63.0, 43.8, 50.6, 39.1, 38.3, 36.1, 36.0, 30.8, 25.3, 22.6, 21.4, 21.0,19.6, 19.2, 16.7, 15.5, 14.6, 11.1, 7.6.

Step 45c: Compound of Formula 8-1: V is N—Ac, X_(A)═OH, X_(B)═H,X_(H)═Br, R₂′═Ac

A suspension of bromomethyltriphenylphosphonium bromide (443 mg, 1.01mmol) in THF (4.0 mL) was treated with sodium bis(trimethylsilyl)amide(1.0 M in THF, 1.00 mL, 1.00 mmol) at −78° C. under nitrogen. Themixture was stirred at −70˜−60° C. for 1 hour before a solution of thecompound from Step 45b (127 mg, 0.18 mmol) in THF (5.0 mL) was added.The reaction mixture was warmed to room temperature over 1 hour andstirred at that temperature for 5 hours. The mixture was thenpartitioned between ethyl acetate and water. The organic extract waswashed with water and brine, dried over Na₂SO₄, and condensed in vacuo.Purification by flash chromatography (SiO₂, hexanes:acetone/9:1˜1.5:1)gave the title compound (87 mg, 62% yield) as a 2.5˜4:1 mixture ofdouble bond isomers.

MS (ESI) m/z 789/791 (M+H)⁺

Step 45d: 2-(2-pyridine)thiophenyl-5-bromide

A solution of 2-(2-thiophenyl)pyridine (3.00 g, 18.6 mmol) in CH₂Cl₂ (90mL) was added dropwise to a solution of bromine (0.95 mL) in CH₂Cl₂ (5mL) at 0° C. The mixture was warmed to room temperature with vigorousstirring over 1.5 hours before dilution with CH₂Cl₂ (200 mL). Themixture was washed with saturated NaHCO₃, Na₂SO₃, brine and dried overNa₂SO₄. Evaporation gave the title compound (4.40 g, 100%).

MS (ESI) m/z 240, 242 (M+H)⁺¹³C NMR (CDCl₃): δ 152.0, 149.8, 146.5,136.9, 131.1, 124.6, 122.4, 118.3, 115.3.

Step 45e: 2-(2-pyridine)thiophenyl-5-tributylstannane

A solution of the compound from Step 45d (600 mg, 2.50 mmol) in dry THF(8.0 mL) was treated with n-butyl lithium (1.6 M in hexanes, 1.56 mL,2.50 mL) at −78° C. with stirring for 30 minutes before tri(n-butyl)tinchloride (0.80 mL, 2.95 mmol) was added. The mixture was warmed to roomtemperature over 1.5 hours and then partitioned between ethyl acetateand aqueous saturated NaHCO₃. The organic layer was washed with waterand brine, dried over Na₂SO₄, and condensed in vacuo. Purification byflash chromatography (SiO₂, hexanes:ethyl acetate/98:2) gave the titlecompound (998 mg, 89% yield).

MS (ESI) m/z 448/449/450/451/452 (M+H)⁺¹³C NMR (CDCl₃): δ 152.7, 150.1,149.6, 140.4, 136.6, 136.3, 125.6, 121.5, 118.8, 28.9, 27.2, 13.6, 10.8.

Step 45f: Compound of Formula 9-2: V is N—Ac, X_(A)═OH, X_(B)═H,R₁₁═2-(2pyridyl)-thiophen-5-yl, R₂′═Ac

A solution of the compound from Step 42c (210 mg, 0.26 mmol), thecompound from Step 45e (150 mg, 0.33 mmol), andtetrakis(triphenylphosphine)palladium (61 mg, 0.05 mmol) in toluene (8.0mL) was degassed and then stirred under nitrogen for 14 hours at 100° C.The resulting material was purified by flash chromatography (SiO₂,hexanes:acetone/9:1˜1:1.5) to give the title compounds as a 1:3.8mixture of double bond isomers (140 mg, 61% yield).

MS (ESI) m/z 870 (M+H)⁺

Step 45g: Compound of Formula I: A and B Taken Together with the CarbonAtom to Which They are Attached are C═CH-2-(2pyridyl)-thiophen-5-yl, Xand Y Taken Together with the Carbon Atom to Which They are Attached areC═N—Ac, L═CH₂CH₃, Z═H, and R₂′═Ac

A solution of the compound from Step 45f (140 mg, 0.16 mmol) in CH₂Cl₂(5.0 mL) was treated with Dess-Martin periodinane (122 mg, 0.29 mmol)for 1 hour at room temperature and then partitioned between ethylacetate and aqueous saturated NaHCO₃:Na₂S₂O₃/3:1. The organic layer waswashed with water and brine. After drying over Na₂SO₄ and evaporationthe crude title compound was obtained as a 1:3.8 mixture of double bondisomers (140 mg, 100% yield).

MS (ESI) m/z 868 (M+H)⁺

Step 45h: Compound of Formula I: A and B Taken Together with the CarbonAtom to Which They are Attached are C═CH-2-(2pyridyl)-thiophen-5-yl, Xand Y Taken Together with the Carbon Atom to Which They are Attached areC═N—Ac, L═CH₂CH₃, Z═H, and R₂′═H

A solution of the compound from Step 45g (140 mg, 0.16 mmol) in methanol(4.0 mL) was stirred at room temperature for 64 hours and then condensedin vacuo. Purification by flash chromatography (SiO₂, CH₂Cl₂:2 M NH₃ inMeOH/99:1˜96:4) gave the title compound as a 1:3 mixture of double bondisomers (97 mg, 73%).

MS (ESI) m/z 826 (M+H)⁺

Example 46

Compound of Formula I: A and B Taken Together with the Carbon Atom toWhich They are Attached are C═O, X and Y Taken Together with the CarbonAtom to Which They are Attached are C═N—Ac, L═CH₂CH₃, Z═F, and R₂′═Ac.

Step 46a: Fluorination of the 3 Position.

To a solution of the 3-keto compound of Example 1 (12.04 g, 17.0 mmol)in anhydrous DMF (70 mL) at 0° C., sodium hydride (60% in mineral oil,1.50 g, 37.5 mmol) was added in one portion. Then the cooling bath wasremoved following the addition of sodium hydride. The reaction mixturewas allowed to stir at room temperature for 30 minutes, during whichperiod the reaction mixture turned into greenish color and then to lightyellow. Upon recooling to 0° C., N-fluorobenzenesulfonimide (5.90 g,18.7 mmol) was added as solid and stirred at 0° C. for 2 hours. Then itwas diluted with isopropyl acetate (600 mL), washed with water (200mL×2), dried (Na₂SO₄), and evaporated. The residue was purified by flashcolumn chromatography (silica gel, acetone/hexanes, 40:60) to give 7.77g (63%) of the title compound as a white solid.

¹³C-NMR (125 MHz, CDCl₃): δ 205.1, 204.9, 184.1, 177.1, 170.0, 165.1,164.9, 141.9, 125.3, 101.6, 99.8, 98.2, 79.8, 79.3, 78.5, 76.1, 71.9,71.0, 69.4, 65.5, 63.4, 41.2, 40.8, 38.8, 31.1, 30.8, 25.3, 24.4, 24.3,23.0, 21.6, 21.3, 20.9, 17.3, 14.5, 12.5. MS (ESI) m/z═727 (M+H)⁺.

Step 46b: Deprotection of 2′-Hydroxy

The fluorinated compound from Step 46a is refluxed in MeOH according tothe procedure set forth in Example 2 to yield the 2′ hydroxy compound.

Step 46c: Ozonolysis

The compound prepared in Step 46b is converted to the title compound viaozonolysis according to the procedure elucidated in Example 3.

Example compounds 47–114 of the formula A:

-   -   wherein Ar₁, Ar₂, M, Q, and Z are as delineated for each example        in Table A.

Example compounds 47–114, where Z═H, are made from the title compound ofExample 3 and the appropriate hydroxylamine of formula Ar₂—M—Ar₁—O—NH₂via the method delineated in Example 4.

Example compounds 47–114, where Z═F, are made from the title compound ofExample 46 and the appropriate hydroxylamine of formula Ar₂—M—Ar₁—O—NH₂via the method delineated in Example 4.

In all of the following examples a mixture of E and Z isomers arepresent which may be separated by HPLC.

The substituted hydroxylamines used in the following examples are eithercommercially available or can be made from readily-available startingmaterials via synthetic methods well known by one of ordinary skill inthe art.

TABLE A MS (ESI): m/z Example Q -Ar₁-M-Ar₂ Z (M +H)⁺ ¹³C NMR (125 MHz,CDCl₃): δ Example 47. Ac

H 774 N/A Example 48. Ac

H 819 N/A Example 49. Ac

H 800 N/A Example 50. Ac

H 775 N/A Example 51. Ac

H 857 N/A Example 52. Ac

H 825 N/A Example 53. Ac

H 825 N/A Example 54. Ac

H 775 N/A Example 55. MOM

H 792 N/A Example 56. Ac

H 760 N/A Example 57. Ac

H 787 N/A Example 58. Ac

H 802 N/A Example 59. Ac

H 800 N/A Example 60. Ac

H 858 N/A Example 61. Ac

H 799 N/A Example 62. Ac

H 799 N/A Example 63. Ac

H 809 N/A Example 64. Ac

H 819 N/A Example 65. Ac

H 810 N/A Example 66. Ac

H 857 N/A Example 67. Ac

H 790 N/A Example 68. Ac

H 832 N/A Example 69. Ac

H 842 N/A Example 70. Ac

H 862 N/A Example 71. Ac

H 840 N/A Example 72. Ac

H 858 N/A Example 73. Ac

H 840 N/A Example 74. Ac

H 815 N/A Example 75. Ac

H 825 N/A Example 76. Ac

H 844 N/A Example 77. Ac

H 857 N/A Example 78. Ac

H 789 N/A Example 79. Ac

H 856 N/A Example 80. Ac

F 841 N/A Example 81. H

H 732 N/A Example 82. Ac

H 817 N/A Example 83. Ac

F 835 N/A Example 84. Ac

H 847 N/A Example 85. Ac

H 831 N/A Example 86. Ac

H 800 N/A Example 87. Ac

H 832 N/A Example 88. Ac

H 871 N/A Example 89. Ac

H 809 N/A Example 90. H

H 816 N/A Example 91. H

H 799 N/A Example 92. OMe

H 805 N/A Example 93. MOM

H 835 N/A Example 94. —OCH₂CN

H 830 N/A Example 95. —OCH₂CH₂OH

H 837 N/A Example 96. H

H 747 N/A Example 97. Ac

H 789 N/A Example 98. Ac

H 939 N/A Example 99. Ac

H 841 N/A Example 100. Ac

H 722 N/A Example 101. Ac

H 881 N/A Example 102. Ac

H 849 N/A Example 103. Ac

H 862 N/A Example 104. Ac

H 851 N/A Example 105. Ac

H 790.55 N/A Example 106. Ac

H 842 N/A Example 107. Ac

H 843 N/A Example 108. Ac

H 872 N/A Example 109. Ac

H 790 N/A Example 110. Ac

H 885 N/A Example 111. Ac

H 815 N/A Example 112. Ac

H 893 N/A Example 113. Ac

H 825 N/A Example 114. Ac

H 900 N/A

Example compounds 115–263 of formula A1:

-   -   wherein Ar₁, Ar₂, M, Q, and Z are as delineated for each example        in Table A1.

Example compounds 115–262, where Z═H, are made from the title compoundof Example 3 and the appropriate hydroxylamine of formulaAr₂—M—Ar₁—O—NH₂ via the method delineated in Example 4.

Example compounds 115–262, where Z═F, are made from the title compoundof Example 46 and the appropriate hydroxylamine of formulaAr₂—M—Ar₁—O—NH₂ via the method delineated in Example 4.

The Examples described in Table A1 are single isomers of the Edesignation, which are separated from the E/Z mixture via silicachromatography or HPLC.

The substituted hydroxylamines used in the following examples are eithercommercially available or can be made from readily-available startingmaterials via synthetic methods well known by one of ordinary skill inthe art.

TABLE A1 MS (ESI): m/z ¹³C NMR (125 MHz. CDCl₃) Example Q -Ar₁-M-Ar₂ Z(M + H)⁺ δ Example 115. Ac

H  857 205.8, 184.7, 178.1, 169.3,156.2, 153.9, 149.7, 145.3,142.9,136.8, 128.3, 124.5,122.0, 119.0, 103.0. Example 116. Ac

H  864 Selected data: 205.7, 184.7,178.0, 167.7, 154.5, 147.1,145.1,138.6, 136.6, 103.1,79.1, Example 117. Ac

H  792 Selected:205.8, 184.8, 178.0, 167.8,153.8, 140.9, 134.5,130.0,123.5, 114.9, 114.7(2), 114.5,110.0, 103.0, 79.4, 76.7, 75.3,74.7,70.5, 69.7, 66.1, 63.1,62.9, 50.7, 46.2, 40.5, 38.8,32.0, 29.9, 28.5,25.4, 23.8,21.5, 20.3, 19.5, 17.8, 15.1,14.1, 13.7, 12.8. Example 118.Ac

H  857 205.8, 184.7, 178.0, 167.7,154.0, 148.6, 147.0, 141.5,141.0,133.0, 130.7, 128.2,124.0, 123.8, 103.1, 79.3, 79.1,76.7, 75.5, 74.5,70.7, 70.5,69.7, 66.0, 63.1, 62.8, 50.7,46.2, 40.4, 38.7, 37.2,31.1,29.5, 28.5, 25.3, 23.8, 21.5,20.3, 19.5, 17.8, 15.0, 14.1,13.7,13.0. Example 119. Ac

H  858 205.8, 184.7, 178.1, 167.8,154.2, 148.8, 144.8, 144.2,142.5,141.6, 140.7, 128.0,125.7, 103.1, 79.5, 79.2, 76.8,75.6, 74.5, 70.9,70.5, 69.8,66.1, 63.1, 62.9, 50.7, 46.2,40.5, 38.8, 37.3, 29.5,28.5,25.4, 23.9, 21.5, 20.3, 19.5,17.8, 15.1, 14.1, 13.6, 13.0. Example120. Ac

H  775 Selected:84.5, 177.6, 167.7, 154.1,149.7, 147.3, 121.9,102.8,79.1, 76.5, 75.3, 73.9, 70.3,69.5, 65.8, 62.8, 62.7, 50.5,46.1,40.2, 38.5, 28.2, 25.1,23.6, 21.2, 20.0, 19.3, 17.5,14.9, 13.8, 13.4,12.7. Example 121. Ac

H  842 205.8, 184.7, 178.0, 170.0,167.8, 163.3, 154.8, 150.0,148.8,137.0, 124.6, 124.6,121.9, 103.0, 102.5, 7935,79.2, 76.8, 74.6, 70.4,69.6,66.9, 66.2, 63.0, 62.7, 50.7,46.1, 40.5, 38.8, 28.7, 25.4,23.9,21.5, 20.2, 19.5, 17.8,15.1, 14.1, 13.6, 13.0. Example 122. Ac

H  831 205.7, 184.8, 178.0, 169.8,167.9, 155.4, 154.9, 139.9,137.4,103.1, 102.2, 79.5, 79.3,76.7, 74.7, 70.5, 69.7, 66.7,66.0, 62.9, 62.7,50.7, 46.1,40.4, 38.7, 28.5, 25.3, 23.9,21.5, 20.2, 19.5, 17.8,15.1,14.0, 13.6, 13.0, 10.9. Example 123. Ac

H  858 N/A Example 124. Ac

H  858 205.8, 184.7, 178.1, 167.8,161.8, 157.4, 154.1, 145.6,143.3,128.9, 127.8, 118.6,103.1, 79.5, 79.2, 76.8, 75.5,74.5, 71.1, 70.5,69.7, 66.1,63.1, 62.9, 50.7, 46.2, 40.5,38.8, 37.3, 31.2, 28.5,25.3,23.9, 21.5, 20.3, 19.5, 17.8,15.1, 14.1, 13.6, 13.0. Example 125.Ac

H  825 Selected:205.8, 184.6, 177.9, 167.9,156.8, 153.7, 142.0,136.6,130.2, 127.4, 127.2, 126.4,121.3, 103.0, 79.2, 76.6, 76.3,74.9,70.5, 69.7, 66.0, 63.1,62.8, 50.8, 46.2, 40.4, 38.7,28.4, 25.3, 23.7,21.4, 20.3,19.6, 17.7, 15.1, 14.1, 13.7,12.7. Example 126. Ac

H  831 Selected:205.8, 184.8, 178.0, 169.5,167.7, 155.2, 153.3,135.3,126.1, 125.2, 123.3, 121.9,103.1, 79.3, 76.7, 74.7, 73.5,70.5,69.8, 66.1, 62.9, 50.7,40.5, 38.8, 28.5, 25.4, 23.8,21.5, 20.3, 19.5,17.7, 15.1,14.1, 12.9. Example 127. Ac

H  843 205.8, 184.8, 177.7, 167.9,159.3, 155.8, 154.6, 136.6,134.5,120.7, 102.9, 79.3, 76.7,75.0, 70.4, 69.7, 67.9, 66.2,62.9, 62.8, 50.8,46.3, 40.5,38.8, 28.7, 25.4, 23.8, 25.4,23.8, 21.5, 20.2, 19.5,17.7,15.1, 14.1, 13.7, 12.9. Example 128. Ac

H  780 N/A Example 129. Ac

H  904 N/A Example 130. Ac

H  829 Selected:205.8, 184.6, 177.5, 168.2;154.8, 147.2, 145.6,144.2,135.6, 128.0, 118.3, 103.0,79.4, 79.1, 76.5, 75.5, 72.0,70.5,69.7, 66.1, 63.0, 62.9,50.8, 46.4, 43.0, 40.5, 38.7,28.5, 25.4, 23.5,21.5, 20.2,19.7, 17.7, 15.2, 14.1, 13.8,12.6. Example 131. Ac

H  830 Selected:205.7, 184.6, 177.3, 168.4,155.2, 152.6, 151.6,148.6,147.1, 134.2, 103.1, 79.5, 79.1,76.5, 75.9, 71.8, 70.5, 69.8,66.1,63.0, 50.8, 43.1, 40.5,38.7, 28.5, 25.5, 23.5, 21.5,19.8, 17.7, 15.2,14.0, 12.6. Example 132. Ac

H  854 E oxime isomer:Selected:205.6, 184.6, 177.9, 167.9,153.8, 145.0,137.5, 128.9128.6, 127.9, 127.3, 121.3,103.2, 9.2, 76.6, 75.9,74.6,70.5, 69.7, 67.2, 66.0, 63.1,62.4, 50.7, 50.1, 46.3, 40.6,38.7,28.6, 25.3, 23.6, 21.5,20.3, 19.6, 17.7, 15.0, 14.1,12.8. Example 133.Ac

H  871 206.0, 184.6, 178.0, 167.8,153.6, 153.0, 149.7, 148.1,143.9,136.7, 125.6, 124.2,121.9, 118.8, 102.9, 78.7, 76.7,74.8, 70.4, 69.6,66.2, 63.3,51.0, 40.5, 38.9, 29.9, 28.9,25.4, 23.6, 23.3, 22.7,22.2,21.5, 20.4, 19.7, 17.7, 15.1,14.2, 12.6, 11.7. Example 134. Ac

H  871 205.9, 184.7, 178.2, 167.7,153.4, 153.0, 150.2, 149.7,143.8,136.7, 125.6, 124.2,121.9, 118.8, 102.6, 78.9, 76.9,74.4, 70.3, 69.2,66.5, 63.2,62.7, 50.7, 46.0, 40.5, 38.9,29.6, 29.5, 25.3, 23.6,22.2,21.4, 20.3, 19.4, 17.9, 15.1,14.3, 13.5, 12.6. Example 135. Ac

H  848 205.8, 184.7, 178.1, 171.8,168.1, 167.8, 154.8, 132.3,132.1,128.7, 125.9, 102.9,79.4, 76.7, 74.6, 70.5, 69.7,67.0, 66.1, 62.9, 62.7,50.7,46.1, 40.5, 38.8, 28.5, 25.3,23.9, 21.5, 20.2, 19.5, 17.8,15.1,14.1, 12.9. Example 136. Ac

H  823 205.6, 184.5, 177.8, 167.6,163.3, 154.2, 146.5, 137.3,129.3,126.8, 102.9, 79.2, 76.5,74.4, 70.4, 70.3, 69.6, 69.5,65.8, 62.8, 62.6,53.8, 50.8,50.5, 46.1, 40.2, 38.5, 31.7,29.3, 28.3, 25.1, 23.6,21.3,20.1, 19.3, 17.5, 14.8, 13.9,12.8. Example 137. Ac

H  774 205.9, 184.8, 178.0, 167.8,153.3, 138.1, 128.4, 128.2,127.8,102.9, 79.4, 76.8, 76.2,74.6, 70.5, 69.6, 66.2, 63.2,62.9, 50.8, 40.5,38.8, 28.7,25.3, 23.8, 21.5, 20.3, 19.5,17.8, 15.1, 14.1, 12.8. Example138. Ac

F  843 205.3, 205.1, 184.2, 153.6,149.8, 146.3, 136.5, 136.3,128.4,128.2, 127.5, 126.4,121.2, 104.1, 99.7, 98.1, 79.6,76.6, 73.7, 72.8,70.7, 69.4,66.0, 63.3, 62.7, 41.2, 40.5,39.1, 28.4, 25.3, 24.7,24.5,23.2, 21.4, 21.1, 17.4, 15.1,14.3, 12.5. Example 139. Ac

H  857 205.8, 184.8, 178.0, 167.7,154.5, 153.9, 149.7, 139.4,138.6,136.8, 128.6, 124.9,123.3, 121.8, 103.1, 79.2, 76.7,74.7, 70.5, 70.2,69.7, 66.1,63.1, 63.0, 50.9, 46.4, 40.5,38.8, 28.5, 25.4, 23.7,21.5,20.4, 19.6, 17.7, 15.1, 14.1,13.8, 12.7. Example 140. Ac

F  876 205.2(d), 184.1, 177.4,165.1(d), 161.7, 157.4, 154.3,145.3,143.4, 128.9, 127.8,118.6, 104.0, 99.8, 98.1, 79.8,76.6, 73.6, 71.2,70.6, 69.7,66.1, 63.2, 62.7, 41.3, 40.5,39.0, 29.9, 28.7, 25.3,24.6,24.4, 23.2, 21.4, 21.0, 17.4,15.0, 14.3, 12.8. Example 141. Ac

F  876 (205.1, 204.9), 183.9, 176.5,(164.9, 164.7), 154.1, 148.6,144.2,144.0, 142.3, 141.4,140.5, 127.7, 125.5, 103.9,(99.5, 97.9), 79.5, 76.3,73.4,70.7, 70.4, 69.6, 65.8, 62.9,62.4, 53.8, 41.1, 40.2, 38.7,29.7,29.3, 28.2, 25.1, 24.4,24.2, 23.0, 21.2, 20.8, 17.1,14.8, 14.1, 12.6.Example 142. Ac

F  841 N/A Example 143. Ac

H  914 205.9, 184.8, 178.0, 169.0,167.8, 154.0, 151.1, 151.0,144.4,143.2, 139.2, 127.3,124.5, 114.6, 111.6, 102.8,79.4, 79.3, 76.8, 74.6,71.1,70.4, 69.4, 66.4, 63.0, 62.8,50.8, 46.1, 40.5, 38.8, 29.9,29.1,25.4, 25.0, 23.8, 21.4,20.3, 19.5, 17.8, 15.1, 14.2,13.8, 12.9. Example144. Ac

H  900 205.8, 184.7, 178.1, 167.8,160.2, 154.5, 151.5, 148.1,147.6,138.7, 138.6, 129.0,127.2, 120.1, 114.4, 103.1,79.5, 79.2, 76.8, 74.6,70.7,70.5, 69.8, 66.1, 63.1, 62.8,50.7, 46.3, 40.5, 38.8, 28.5,25.3,23.9, 21.5, 20.3, 19.5,17.8, 15.1, 14.1, 13.6, 13.0 Example 145. Ac

H  913 205.6, 184.5, 177.8, 167.6,161.8, 154.1, 145.5, 138.2,138.1,128.8, 128.2, 127.9,127.6, 126.8, 102.8, 79.2, 76.5,74.3, 70.4, 70.3,69.5, 65.9,62.8, 62.6, 50.5, 46.0, 44.0,40.2, 38.5, 29.3, 28.3,25.1,23.6, 21.3, 20.0, 19.3, 17.5,14.8, 13.9, 13.4, 12.8. Example 146.Ac

H  817.28 205.9, 184.8, 169.4, 167.9,153.9, 142.6, 132.7, 103.1,79.4,75.3, 74.8, 70.5,69.7, 66.1, 63.1, 63.0,50.8, 38.8, 28.5, 25.3,23.8,21.5, 20.3, 19.6,17.8, 15.1, 14.1, 12.9 Example 147. Ac

H  818 Selected:205.6, 184.4, 168.4, 168.3,157.0, 150.8, 148.1,138.8,120.3, 114.2, 110.0, 103.1,78.3, 76.5, 72.7, 70.5, 69.8,66.1,62.5, 62.1, 50.9, 40.4,31.2, 28.5, 25.4, 23.3, 21.5,19.8, 18.4, 15.1,14.2, 11.9. Example 148. Ac

F  836 Selected:203.1, 202.8, 181.8, 175.1,165.9, 163.2, 163.0,154.8,148.5, 146.0, 136.7, 118.3,112.0, 102.0, 76.8, 72.6, 70.6,68.5,67.8, 63.9, 38.3, 26.3,19.3, 19.3, 16.3, 12.9, 9.7. Example 149. Ac

H  899 205.8, 184.8, 178.0, 167.8,160.1, 154.4, 146.6, 138.8,137.9,129.3, 129.3, 128.9,127.2, 124.7, 120.4, 103.1,79.5, 76.8, 74.6, 70.7,70.5,69.8, 69.7, 66.1, 63.1, 62.9,54.0, 50.7, 40.5, 38.8, 32.0,29.9,29.5, 28.6, 25.4, 23.9,21.5, 20.3, 19.5, 17.8, 15.1,14.1, 13.0. Example150. Ac

F  835.39 205.4, 184.3, 169.3, 154.1142.4, 132.7, 128.4, 127.9127.6,104.1, 79.7, 76.6,66.1, 62.6, 41.3, 40.5,28.5, 25.3, 23.2, 21.4,21.0,17.4, 12.7 Example 151. Ac

H  808 205.5, 184.5, 182.9, 177.7,167.6, 154.4, 151.6, 143.5,136.2,126.9, 102.8, 79.2, 79.0,76.5, 74.3, 70.5, 70.2, 69.4,65.9, 62.7, 50.6,45.9, 40.2,38.5, 28.4, 25.1, 23.6, 21.2,20.0, 19.2, 17.5, 14.8,13.8,13.3, 12.8 Example 152. Ac

H  823 N/A Example 153. Ac

H  893 205.9, 184.9, 177.8, 167.9,165.9, 153.9, 142.4, 138.3,134.4,129.3, 128.2, 127.3,124.7, 120.4, 102.8, 79.4, 79.2,76.7, 75.3, 74.9,70.4, 69.5,66.3, 63.1, 63.0, 50.7, 46.2,40.5, 38.8, 32.0, 28.9,25.3,23.8, 21.4, 20.3, 19.5, 17.8,15.1, 14.1, 13.6, 12.9. Example 154.Ac

H  894 N/A Example 155. Ac

H  845 205.9, 184.8, 178.0, 171.8,167.8, 153.7, 139.8, 135.7,129.9,127.9, 127.3, 103.0,79.4, 79.2, 76.8, 75.6, 74.7,70.5, 69.7, 66.1, 63.1,62.9,50.7, 46.2, 40.5, 38.8, 28.5,25.4, 23.8, 21.5, 20.3, 19.5,17.8,15.1, 14.1, 13.7, 12.9. Example 156. Ac

H  808 205.5, 184.8, 177.7, 168.4,164.3, 156.3, 151.8, 103.2,99.9, 79.4,79.2, 76.8, 75.2,71.1, 70.5, 69.6, 66.0, 62.9,62.7, 50.7, 46.4, 40.4,38.7,29.9, 28.6, 25.4, 23.5, 21.5,20.2, 19.6, 17.9, 15.0, 14.0,13.7,12.7. Example 157. Ac

H  831.60 205.8, 184.8, 177.9, 168.3,167.9, 153.8, 141.8, 134.0,128.0,127.0, 103.0, 79.4,79.2, 76.7, 75.4, 74.8,70.5, 69.8, 66.1, 63.1,63.0,50.7, 46.2, 40.5,23.8, 21.5, 20.3, 19.5,17.8, 15.1, 14.1, 13.7,12.9Example 158. Ac

H  845.61 205.8, 184.8, 177.9, 167.8,167.5, 153.8, 141.7, 134.2,128.0,127.0, 103.0, 79.4, 79.2,76.7, 75.4, 74.7,70.5, 69.7, 66.1, 63.1,63.0,50.7, 46.2, 40.5,38.8. 35.1, 28.5, 25.3,23.8, 21.5, 20.3, 19.5,17.8,15.1. 14.1, 13.7,12.9 Example 159. Ac

H  832 204.6, 183.5, 176.7, 166.6,166.0, 152.6, 142.3, 128.5,128.2,126.4, 101.8, 78.1,77.9, 75.5, 74.2, 73.4,69.2, 68.5, 64.8, 61.8,61.7,51.0, 49.5, 45.0,39.2, 37.5, 27.3, 24.1,22.6, 20.2, 19.0, 18.3,16.5,13.9, 12.8, 12.4,11.6 Example 160. Ac

H  857 205.8, 184.8, 177.9, 168.9,167.8, 153.8, 142.0, 133.8,128.0,127.0, 103.0, 79.4, 76.7,75.4, 74.8, 70.5, 63.0,50.7, 46.2, 40.5,38.8,28.5, 25.3, 23.8, 23.3,21.5, 20.3, 19.5, 17.8,15.1, 14.1, 13.7,12.9,7.0 Example 161. Ac

H  913 N/A Example 162. Ac

H  899 N/A Example 163. Ac

H  837 N/A Example 164. Ac

H  872 205.9, 184.7, 178.1, 167.7,158.2, 153.7, 151.2, 145.6,142.0,138.5, 127.7, 124.0,109.3, 107.1, 102.7, 79.5, 79.1,76.8, 74.6, 71.1,70.3, 69.3,66.5, 63.1, 62.9, 50.8, 46.0,40.6, 38.8, 29.9, 29.3,25.4,23.8, 21.4, 20.3, 19.5, 17.8,15.1, 14.2, 13.5, 13.0. Example 165.Ac

H  817 205.5, 184.7, 177.4, 168.7,168.2, 157.0, 137.4, 128.9,124.8,121.4, 103.0, 79.7, 78.9,76.6, 75.9, 73.6, 70.5, 69.7,63.0, 62.9, 51.0,46.4, 40.5,38.7, 36.9, 28.6, 25.3, 23.4,21.5, 20.3, 19.7, 17.7,15.2,14.2, 12.3. Example 166. Ac

H  916 205.8, 184.6, 176.6, 169.3,156.2, 149.3, 148.9, 145.5,138.8,128.4, 128.0, 122.1,118.7, 111.7, 109.7, 102.4,79.6, 79.0, 76.2, 75.4,71.0,70.6, 70.4, 69.5, 66.3, 58.4,56.22, 56.20, 50.9, 45.2, 40.5,39.6,39.0, 36.8, 29.9, 28.9,25.5, 23.4, 21.5, 20.2, 19.7,17.2, 15.7, 14.5,12.8, 12.0. Example 167. Ac

H  862 205.8, 184.8, 177.9, 167.8,156.9, 153.6, 132.3, 130.3,128.2,122.0, 110.9, 103.0,79.3, 79.2, 76.7, 74.8, 71.0,70.5, 69.7, 66.0, 63.1,55.7,52.3, 50.8, 46.2, 40.4, 38.8,28.5, 25.3, 23.8, 21.4, 20.3,19.6,17.7, 15.1, 14.1, 13.7,12.8 Example 168. Ac

H  847 205.8, 184.9, 177.8, 169.4,167.8, 157.3, 153.6, 133.7,131.3,128.4, 118.7, 109.7,103.0, 79.3, 79.2, 76.7, 75.0,70.9, 70.4, 69.7,66.0, 63.0,55.7, 50.8, 46.2, 40.4, 38.7,28.4, 25.3, 23.8, 21.4,20.3,19.6, 17.7, 15.0, 14.0, 13.7,12.8. Example 169. Ac

H  831 204.7, 183.5, 176.8, 167.2,166.5, 152.0, 136.3, 132.8,127.9,118.6, 101.5, 78.1, 77.8,75.5, 74.5, 73.4, 69.1, 68.1,65.2, 61.9, 61.6,52.4, 49.5,44.8, 39.3, 37.6, 30.8, 28.7,28.0, 24.1, 23.6, 22.5,20.1,19.0, 18.2, 16.5, 13.9, 12.9,12.3, 11.6. Example 170. Ac

H  805 205.5, 184.4, 177.7, 167.6,154.6, 148.7, 137.2, 126.4,114.3,109.6, 102.9, 79.1, 76.4,74.3, 70.2, 69.8, 69.5, 65.8,62.7, 62.5, 50.4,46.1, 40.2,38.5, 28.2, 25.1, 23.5, 21.2,20.0, 19.2, 17.5, 14.8,13.8,12.7 Example 171. Ac

H  832 205.8, 184.8, 177.9, 168.7,167.9, 153.9, 142.4, 132.0,128.1,127.1, 79.3, 76.7,75.3, 74.8, 70.5, 69.7,66.0, 63.0, 50.8, 46.3,40.4,38.7, 28.5, 25.3,23.8, 21.5, 20.3, 19.5,17.8, 15.1, 14.1, 13.7,12.9Example 172. Ac

H  847 203.7, 182.6, 175.9, 165.6,151.1, 135.4, 131.0, 127.2,116.5,100.8, 77.2, 77.1, 74.6,73.7, 72.5, 68.3, 67.6, 64.0,61.0, 60.8, 50.4,48.6, 44.0,38.3, 36.7, 27.8, 26.4, 23.2,21.6, 19.3, 18.2, 17.4,15.6,13.0, 12.0, 11.5, 10.7. Example 173. Ac

F  890 (205.1, 204.9), 183.9, 164.4,158.0, 153.8, 151.0, 145.5,141.5,138.2, 127.4, 123.7,109.1, 106.8, 103.9, 99.5, 97.9,79.5, 76.3, 73.3,71.0, 70.4,69.6, 65.8, 62.9, 62.4, 41.0,40.2, 29.7, 28.2, 25.1,24.4,24.2, 23.0, 21.2, 20.8, 17.1,14.8, 14.0, 12.5. Example 174. Ac

F  932 Selected data:(205.1, 204.9), 184.0, 168.7,154.1, 150.8, 144.2,139.0,124.1, 111.6, 103.9, 79.3, 73.4,71.1, 70.4, 69.6, 65.8, 62.3,41.0,40.2, 29.7, 28.2, 25.1,22.9, 21.2, 17.2, 14.9, 14.0,12.3. Example 175.Ac

H  831 N/A Example 176. Ac

H  818 205.9, 184.8, 178.1, 173.2,167.8, 153.6, 141.9, 129.9,127.4,102.5, 79.4, 79.1, 76.8,75.7, 74.7, 70.1, 68.8, 66.3,63.1, 62.9, 50.7,46.1, 39.9,38.8, 29.9, 29.6, 25.4, 23.8,21.4, 20.3, 19.5, 17.8,15.1,14.2, 13.6, 12.9. Example 177. Ac

H  800 205.8, 184.7, 178.0, 167.8,153.4, 137.8, 136.9, 128.5,126.4,113.9, 103.0, 79.4,76.7, 75.9, 74.6, 70.5,69.7, 66.0, 63.1, 50.8,40.5,38.8, 28.5, 25.3,23.8, 21.5, 20.3, 19.5,17.8, 15.1, 14.1, 13.7,12.9Example 178. Ac

H  876 205.8, 184.7, 178.0, 167.8,164.0, 162.1, 154.1, 144.7,144.6,141.6, 139.7, 138.7,138.6, 128.2, 124.1, 110.0,109.7, 103.1, 79.4, 79.3,76.8,75.9, 74.5, 70.7, 70.5, 69.8,66.1, 63.1, 62.9, 50.7, 46.3,40.5,38.8, 28.5, 25.4, 23.8,21.5, 20.3, 19.5, 17.8, 15.1,14.1, 13.7, 13.0.Example 179. Ac

H  801 N/A Example 180. H

H  830 205.2, 170.0, 169.2, 158.3,154.1, 151.2, 145.9, 141.7,138.4,127.9, 124.0, 109.3,107.1, 103.6, 80.5, 79.0, 78.8,75.8, 71.1, 70.6,69.8, 66.1,64.7, 63.0, 51.7, 48.1, 40.5,38.3, 28.4, 23.0, 21.5,21.1,20.2, 17.4, 16.0, 14.4, 14.0,11.9. Example 181. Ac

H  852, 854 205.4, 184.5, 177.6, 169.8,167.3, 153.4, 136.9, 131.3,75.1,74.3, 71.5, 69.0, 63.3,62.8, 50.4, 40.6, 31.6, 30.6,25.1, 23.5, 22.6,21.0, 17.5,14.8, 14.1, 13.7, 12.6. Example 182. Ac

H  852 N/A Example 183. Ac

H  895, 897 205.5, 184.5, 177.7, 169.9,168.5, 167.5, 153.5, 140.3,130.8,130.7, 130.6, 130.0,129.8, 126.4, 123.2, 102.8,101.8, 79.0, 76.5, 75.0,74.9,74.4, 70.2, 69.5, 65.8, 62.8,50.5, 47.4, 45.9, 44.2, 40.3,40.2,38.5, 34.9, 33.3, 30.8,28.2, 25.1, 23.5, 21.2, 17.5,14.8, 14.5, 13.8,12.5. Example 184. Ac

F  918 N/A Example 185. Ac

H  862 205.9, 184.9, 177.5, 168.1,167.0, 155.1, 147.4, 139.1,133.6,132.4, 129.9, 123.9,102.8, 79.5, 79.2, 76.7, 75.7,72.6, 70.4, 69.5,66.2, 63.2,62.9, 60.7, 50.8, 46.3, 40.5,38.7, 29.9, 28.9, 25.4,23.8,21.4, 20.3, 19.7, 17.7, 15.2,14.1, 12.8. Example 186. Ac

H  921 205.53, 184.45, 177.74,169.96, 167.57, 162.00,154.51, 149.41,141.94,139.01, 128.79, 120.30,102.58, 102.51, 79.19, 78.94,76.49, 74.40,70.08, 69.15,66.52, 66.12, 62.72, 62.41,50.42, 45.81, 40.26,38.50,28.87, 25.10, 23.62, 21.15,19.95, 19.18, 17.52, 14.85,13.86, 12.75Example 187. Ac

H  867 205.48, 184.43, 177.67,170.41, 167.61, 161.75,154.70, 150.29,137.87,133.77, 128.81, 124.82,102.70, 102.48, 79.13, 79.00,76.47, 74.41,70.15, 69.35,66.43, 65.91, 62.69, 62.42,50.40, 45.90, 40.21,38.46,30.89, 29.23, 28.44, 25.08,23.59, 21.18, 19.93, 19.20,17.49,14.81, 13.80, 13.31,12.74 Example 188. Ac

H  851 N/A Example 189. Ac

F  904 N/A Example 190. Ac

H  887 205.9, 184.7, 178.1, 167.8,163.7, 153.8, 150.3, 145.6,142.2,139.2, 127.9, 124.1,111.3, 109.1, 103.0, 79.4, 76.8,74.5, 71.1, 70.4,69.6, 66.3,63.1, 62.9, 53.6, 50.8, 46.1,40.5, 38.8, 30.0, 28.8,25.4,23.8, 21.5, 20.3, 19.5, 17.8,15.1, 14.2, 13.6, 12.9. Example 191. H

H  872 205.2, 187.9, 169.3, 169.0,154.5, 151.0, 144.7, 142.9,139.2,127.5, 124.5, 114.7,112.0, 103.6, 80.6, 78.8, 77.8,76.0, 71.1, 70.6,69.8, 66.1,64.7, 63.0, 51.6, 48.1, 41.7,40.5, 38.3, 35.3, 30.0,28.5,25.0, 23.0, 21.5, 21.2, 20.2,17.3, 16.0, 14.4, 14.1, 11.9. Example192. Ac

H  857 205.8, 184.7, 178.0, 167.8,154.0, 152.2, 149.7, 145.0,137.0,131.8, 128.2, 127.7,124.7, 118.6, 103.1, 79.4,74.6, 73.5, 70.5,69.8,66.1, 63.1, 62.8, 50.7,40.5, 28.5, 25.4, 23.8,21.5, 19.5, 17.8,15.1,14.1, 13.0 Example 193. Ac

H  852 205.8, 184.7, 178.1, 167.8,164.9, 157.5, 153.6, 141.0,137.1,128.3, 119.2, 103.0,79.4, 76.8, 75.8, 74.6,63.0, 50.8, 40.5, 38.8,70.5,69.8, 66.1, 63.1,12.9 Example 194. H

H  857 204.82, 169.43, 168.98,166.28, 162.73, 148.03,147.32, 138.23,123.11,121.60, 103.20, 102.74, 80.34,78.59, 75.61, 70.22, 69.43,66.51,65.98, 62.66, 53.92,51.34, 47.70, 40.25, 28.40,22.74, 21.18, 20.88,19.81,17.10, 14.09, 13.75, 11.63 Example 195. Ac

H  913 205.66, 184.49, 177.58,169.88, 167.64, 162.38,154.66, 150.06,147.03,138.27, 124.01, 122.92,102.37, 79.06, 76.46, 74.36,70.13, 69.34,66.40, 65.94,62.63, 62.44, 50.47, 46.02,40.22, 38.45, 35.21,34.34,28.51, 25.06, 23.49, 21.15,19.94, 19.21, 17.46, 15.47,14.95,14.80, 13.79, 12.62 Example 196. H

H  871 204.90, 169.61, 168.96,163.60, 162.46, 154.94,150.06, 146.95,138.29,123.97, 122.96, 103.31, 102.46,80.35, 78.54, 75.61, 70.24,69.52,66.45, 65.86, 62.51, 5135, 47.82, 40.21, 34.33, 28.17,22.72, 21.16,20.82, 19.84,17.09, 15.72, 14.96, 14.06,13.63, 11.63 Example 197. H

H  816 205.1, 169.3, 154.3, 148.8,148.7, 147.1, 141.4, 141.3,133.1,130.7, 128.5, 128.4,124.1, 123.9, 123.8, 103.5,80.6, 78.8, 75.9, 70.8,70.6,69.8, 66.2, 63.0, 51.7, 48.1,40.5, 38.3, 28.5, 23.0, 21.5,21.2,20.1, 17.4, 16.0, 14.4,14.0, 11.9. Example 198. H

H N/A Example 199. Ac

H  853 205.8, 184.7, 178.0, 167.9,154.2, 153.7, 151.3, 149.5,144.6,143.8, 143.6, 137.1,134.6, 121.3, 103.1, 79.4,76.8, 74.7, 73.4,70.5,69.8, 66.1, 63.1, 62.8,50.7, 46.3, 40.5, 38.8,28.5, 25.4, 23.8,21.5,20.3, 19.5, 17.8, 15.1,14.1, 13.7, 13.0. Example 200. Ac

H  882 205.9, 184.6, 176.5, 169.4,156.6, 154.6, 144.7, 142.9,137.7,133.8, 128.4, 126.5,126.4, 122.2, 117.5, 102.5,79.7, 79.1, 76.2, 75.5,70.9,70.4, 69.6, 66.4, 58.5, 50.9,45.4, 40.6, 40.0, 39.1, 36.8,30.0,29.0, 25.6, 23.4, 21.6,20.2, 19.8, 17.3, 15.7, 14.5,12.9, 12.0. Example201. Ac

H  852 205.8, 184.7, 178.0, 167.8156.3, 155.8, 154.0, 149.4,149.2,137.1, 133.7, 123.9,121.3, 120.9, 103.1, 79.4,76.8, 74.6, 73.6,70.5,69.8, 66.1, 63.1, 50.7,40.5, 28.5, 25.4, 23.8,21.5, 19.5, 17.8,15.1,14.1, 13.0 Example 202. H

H  833 N/A Example 203. H

H  775 205.2, 188.5, 169.5, 169.4,154.2, 142.1, 133.0, 128.2,127.8,103.5, 80.5, 78.8, 78.6,77.9, 75.9, 75.6, 70.6, 69.8,66.1, 64.7, 63.0,51.6, 48.0,40.5, 31.2, 28.5, 23.0, 21.4,21.1, 20.0, 17.4, 15.9,14.3,14.0, 11.8 Example 204. H

H  880 204.84, 169.57, 169.01,162.08, 154.68, 149.35,141.96, 139.04,128.85,120.37, 103.17, 102.78, 80.34,78.60, 75.60, 70.23, 69.44,66.54,65.99, 64.25, 62.67,51.34, 47.68, 40.25, 38.08,35.06, 28.41, 22.73,21.18,20.87, 19.80, 17.09, 15.57,14.09, 13.78, 12.63, 11.62 Example 205.Ac

H  858 205.8, 184.7, 178.0, 169.5,167.9, 154.2, 151.0, 149.5,144.3,137.2, 134.7, 121.5,119.5, 103.1, 79.4, 79.2, 76.8,74.7, 73.4, 70.5,69.8, 66.1,63.1, 62.8, 50.7, 46.3, 40.5,38.8, 28.5, 25.4, 23.9,21.5,20.3, 19.5, 17.8, 15.1, 14.1,13.7, 13.0. Example 206. H

H  816 N/A Example 207. Ac

H  885 205.68, 184.54, 177.56,170.00, 167.59, 162.28,154.63, 149.44,147.27,138.27, 124.27, 123.10,102.25, 101.99, 79.11, 78.92,76.41, 74.36,69.71, 68.49,66.43, 66.06, 62.61, 62.36,50.41, 40.29, 38.37,30.01,25.05, 23.48, 20.94, 19.89,19.14, 17.44, 14.76, 13.86,12.63Example 208. Ac

H  790 203.7, 182.6, 175.9, 165.6,156.3, 151.3, 146.7, 137.0,121.1,106.3, 101.0, 77.2, 77.0,74.6, 73.5, 72.5, 71.7, 68.4,67.6, 63.9, 61.0,60.6, 48.6,44.1, 38.3, 36.7, 35.2, 26.4,23.2, 21.6, 19.4, 18.2,17.4,15.7, 12.9, 12.0, 11.5, 10.7. Example 209. Ac

H  800 205.7, 184.7, 177.8, 168.0,154.9, 150.8, 137.9, 136.5,133.0,128.3, 117.5, 103.1,79.3, 76.7, 72.6, 50.6, 46.4,40.5, 38.7. Example210. Ac

H  863 205.5, 184.4, 177.8, 167.5,162.0, 153.8, 143.2, 143.0,137.4,127.1, 126.1, 117.9,102.5, 79.2, 78.9, 76.5, 74.3,70.4, 70.1, 69.2,66.0, 62.8,62.6, 50.4, 45.8, 40.2, 38.5,28.8, 25.1, 23.6, 21.1,20.0,19.2, 17.5, 14.8, 13.9, 13.3,12.7. Example 211. Ac

F  875 Selected data:(205.1, 204.9), 184.0, 168.2,164.7(d), 153.6,143.7, 139.8,132.9, 128.7, 128.3, 126.5,118.7, 103.9, 99.5, 97.9.Example 212. H

F  833 Selected data:(204.3, 204.0), 187.4, 165.8,153.5, 143.7, 139.6,133.1,128.5, 126.6, 118.8, 104.1,99.0, 97.3. Example 213. H

H  821 204.9, 187.4, 169.0, 162.0,154.3, 143.3, 142.7, 137.7,127.4,126.1, 118.1, 103.4,80.3, 78.7, 78.6, 75.6, 70.5,70.3, 69.6, 65.9, 64.4,62.8,51.4, 47.8, 40.3, 38.1, 28.2,22.8, 21.2, 20.9, 19.9, 17.1,15.7,14.1, 13.7, 11.7. Example 214. Ac

F  859 205.1, 204.9, 183.9, 176.7,164.9, 164.7, 154.0, 151.1,147.8,142.0, 138.9, 131.0,127.0, 112.0, 107.1, 103.9,99.5, 97.9, 79.4, 76.3,73.4,73.0, 70.4, 69.6, 65.8, 62.9,62.4, 41.1, 40.2, 38.8, 37.2,30.9,28.2, 25.1, 24.4, 24.2,23.0, 21.2, 20.7, 17.2, 14.8,14.7, 14.1, 12.5Example 215. Ac

H  841 205.8, 184.7, 178.0, 167.8,154.0, 151.3, 148.2, 142.2,139.2,131.3, 127.3, 112.2,107.9, 103.1, 79.3, 79.2, 76.8,75.5, 74.6, 73.2,70.5, 69.8,66.1, 63.1, 62.8, 50.7, 46.2,40.5, 38.8, 37.2, 28.5,25.4,23.8, 21.5, 20.2, 19.5, 17.8,15.1, 14.1, 13.7, 13.0. Example 216.Ac

F  808 Selected:205.3, 205.1, 184.1, 158.4,153.5, 148.7, 139.0,123.2,108.4, 104.2, 99.7, 98.1, 79.6,76.5, 74.0, 73.6, 70.6, 69.9,66.0,63.1, 62.7, 41.3, 40.5,28.4, 25.3, 24.6, 24.4, 23.2,21.4, 21.0, 17.4,15.0, 14.3,12.7 Example 217. Ac

H  979 205.5, 184.4, 177.7, 168.3,167.5, 159.0, 154.3, 152.3,148.8,128.0, 126.0, 114.5,113.6, 105.0, 102.7, 79.1, 78.9,76.4, 74.2, 70.1,69.4, 66.8,65.8, 62.6, 62.4, 61.7, 56.0,50.4, 45.9, 40.1, 38.4,28.3,25.0, 23.5, 21.1, 19.9, 19.1,17.4, 14.7, 13.7, 13.3, 12.8, Example218. Ac

H  886 N/A Example 219. Ac

H  927 205.61, 184.49, 177.64,169.80, 167.64, 156.83,154.72, 130.37,127.62,114.93, 102.60, 101.03, 79.17,76.47, 74.47, 70.11, 69.26,66.47,66.10, 62.68, 62.43,53.41, 50.44, 45.90, 40.26,38.48, 28.70, 25.11,23.59,21.16, 19.94, 19.20, 17.50,14.84, 13.84, 13.31, 12.74 Example 220.Ac

F  876 204.1, 203.9, 183.0, 161.7,152.6, 138.2, 129.1, 128.9,127.5,126.3, 102.9, 98.5,96.9, 78.4, 72.4, 69.4,68.6, 64.8, 61.4, 40.0,39.2,27.1, 24.1, 23.4,23.2, 21.9, 20.2, 19.8,16.1, 13.7, 13.1, 11.4, Example221. Ac

H  872 205.63, 184.51, 177.58,170.82, 167.69, 156.01,155.00, 131.90,127.11,113.71, 111.05, 102.55,101.54, 79.18, 76.46, 74.51,70.06, 69.18,66.34, 69.18,66.34, 62.41, 50.44, 45.93,40.28, 38.47, 25.12,23.59,21.15, 19.94, 19.21, 17.51,14.84, 13.84, 12.76 Example 222. Ac

H  901 205.7, 184.5, 177.8, 168.4,167.5, 159.8, 154.2, 153.2,147.5,124.4, 123.4, 121.0,113.7, 104.6, 101.9, 79.3, 76.5,74.4, 69.8, 68.4,66.6, 60.9,55.9, 50.5, 45.6, 40.1, 38.5,34.6, 30.1, 29.7, 25.1,23.6,21.0, 19.9, 19.1, 17.5, 14.9,13.9, 12.8, 6.6, 5.8, Example 223. Ac

H  858 204.6, 183.5, 176.7, 166.6,161.7, 152.4, 138.4, 129.0,128.9,127.6, 126.3, 101.8,78.1, 75.5, 74.4, 73.4,69.2, 68.5, 64.8, 61.9,61.7,49.5, 45.0, 39.2,37.5, 27.2, 24.1, 22.6,20.2, 19.0, 18.3, 16.5,13.9,12.8, 12.4, 11.7, Example 224. Ac

H  857 205.4, 184.4, 177.6, 169.7,167.3, 153.1, 144.2, 137.1,133.7,132.0, 128.4, 127.9,125.8, 124.6, 123.0, 100.3,79.2, 76.4, 75.5, 74.3,71.5,69.0, 63.3, 62.8, 50.4, 40.6,38.3, 30.5, 25.0, 23.5, 22.6,21.3,21.0, 17.4, 14.8, 14.1,13.7, 12.6. Example 225. Ac

H  842 205.8, 184.7, 177.9, 167.9,054.3, 153.0, 149.1, 148.5,141.8,139.6, 133.3, 112.8,103.1, 79.3, 79.2, 76.8, 74.7,72.9, 70.5, 69.8,66.1, 63.1,62.8, 50.7, 46.3, 40.5, 38.7,28.5, 25.4, 23.8, 21.5,20.2,19.5, 17.8, 15.1, 14.1, 13.7,13.0 Example 226. Ac

H  841 205.8, 184.7, 177.9, 167.9,154.3, 149.3, 148.8, 139.5,135.2,132.2, 130.9, 116.4,112.1, 103.1, 79.3, 79.2, 76.8,75.6, 74.7, 72.8,70.5, 69.8,66.1, 63.1, 62.8, 50.7, 46.3,40.5, 38.7, 37.2, 28.5,25.4,23.8, 21.5, 20.2, 19.5, 17.8,15.1, 14.1, 13.7, 13.0. Example 227.Ac

H  873 205.61, 184.52, 177.70,167.61, 159.73, 153.56,140.14, 129.94,128.25,126.88, 102.69, 79.11, 78.95,75.21, 74.47, 70.18, 69.35,65.88,62.80, 62.67, 50.80,50.52, 46.03, 40.21, 38.51,28.47, 25.10, 23.54,21.17,20.04, 19.28, 17.52, 14.84,13.83, 13.47, 12.62 Example 228. Ac

H  867 205.8, 184.7, 178.0, 167.8,158.2, 156.1, 154.8, 153.9,149.2,138.8, 136.9, 133.2,120.8, 111.9, 109.0, 103.1,79.4, 79.2, 76.8, 75.9,74.6,73.6, 70.5, 69.8, 66.1, 63.1,62.8, 50.7, 46.2, 40.5, 38.8,28.5,25.4, 23.8, 21.5, 20.3,19.5, 17.8, 15.1, 14.1, 13.7,13.0. Example 229.Ac

H  799 205.8, 184.7, 177.9, 167.8,154.2, 150.0, 141.7, 136.2,133.6,127.2, 103.1, 83.0, 79.3,76.7, 74.7, 73.2, 70.5, 69.8,66.1, 63.0, 62.8,50.7, 46.3,40.5, 38.8, 28.5, 25.4, 23.8,21.5, 20.2, 19.5, 17.8,15.1,14.1, 13.7, 13.0. Example 230. H

F  849 N/A Example 231. H

H  825 N/A Example 232. Ac

H  790 N/A Example 233. Ac

H  842 N/A Example 234. Ac

H  797 205.60, 184.52, 177.70,169.21, 167.48, 157.86,154.78, 102.77,79.04, 76.44,74.37, 70.21, 70.17, 69.36,65.87, 62.65, 62.46,50.47,46.05, 40.20, 38.26, 29.66,28.47, 25.10, 23.52, 21.20,20.00,19.26, 17.49, 14.81,13.83, 13.44, 12.70 Example 235. Ac

H  874 205.64, 184.49, 177.63,167.60, 153.94, 149.06,148.90, 136.74,134.40,119.56, 109.74, 102.27, 79.18,76.50, 74.48, 72.98, 69.95,68.88,66.44, 62.81, 62.52,50.45, 45.77, 40.33, 38.53,25.13, 23.58, 21.08,19.96,19.20, 17.55, 14.86, 13.90,13.28, 12.71 Example 236. Ac

H  814 205.8, 184.8, 178.1, 167.7,158.4, 154.1, 140.9, 137.9,117.9,108.9, 103.0, 85.8, 84.4,79.6, 79.2, 76.8, 74.5, 70.5,69.7, 66.1, 63.0,62.8, 62.5,50.7, 46.1, 40.5, 38.8, 28.5,25.4, 24.0, 21.5, 20.3,19.5,17.8, 15.1, 14.1, 13.6, 13.1. Example 237. Ac

H  868 N/A Example 238. Ac

H  872 205.8, 184.8, 178.0, 167.7,156.7, 155.6, 153.8, 140.1,138.9,128.0, 126.1, 125.8,113.6, 112.4, 102.9, 79.3, 79.2,76.7, 76.5, 75.0,70.5, 69.7,66.1, 63.1, 50.8, 46.1, 40.5,38.8, 28.5, 25.4, 23.8,21.5,20.3, 19.6, 17.7, 15.2, 14.2,13.6, 12.8. Example 239. Ac

H  816 205.9, 184.8, 178.0, 167.7,156.3, 155.4, 153.7, 135.6,132.0,117.4, 116.9, 112.9,110.0, 102.9, 79.3, 79.2, 76.7,76.6, 74.9, 70.5,69.7, 66.1,63.1, 50.8, 46.1, 40.5, 38.8,28.5, 25.4, 23.8, 21.5,20.3,19.6, 17.7, 15.2, 14.2, 13.6,12.8. Example 240. Ac

H  816 N/A Example 241. Ac

H  814 N/A Example 242. Ac

H  855 205.8, 184.7, 178.0, 167.8,153.9, 151.4, 148.1, 143.2,,139.2,130.8, 125.8, 118.6,11.8, 103.1, 79.3, 79.2, 77.6,77.5, 77.3, 77.0,76.8, 74.6,73.2, 70.5, 69.7, 66.1, 63.1,62.8, 50.7, 46.2, 40.5,38.8,28.5, 25.4, 23.8, 21.5, 20.3,19.5, 17.8, 15.1, 14.1, 13.6,13.0,9.3. Example 243. Ac

H  818 N/A Example 244. Ac

H  842 205.6, 184.4, 177.6, 167.6,154.1, 148.6, 148.2, 139.2,102.7,79.1, 76.5, 74.4, 72.6,70.1, 69.3, 66.0, 62.8, 62.5,50.4, 46.0, 40.2,38.5, 31.5,28.6, 25.1, 23.5, 22.6, 21.2,19.9, 19.2, 17.5, 14.8,14.1,13.8, 13.4, 12.7. Example 245. Ac

H  874 205.60, 184.57, 177.70,171.97, 167.62, 153.60,153.04, 141.16,129.92,128.23, 125.88, 102.60, 79.15,78.91, 76.49, 75.09, 74.55,62.68,50.48, 45.92, 40.21,38.51, 28.63, 25.12, 23.55,21.17, 20.00, 19.26,17.52,14.88, 13.86, 13.37, 12.65 Example 246. Ac

H  858 205.58, 184.50, 177.67,168.20, 167.57, 153.61,151.03, 141.67,128.46,128.08, 102.60, 79.14, 78.90,76.48, 75.11, 74.45, 70.14,69.29,66.02, 62.82, 62.65,50.47, 40.25, 38.52, 28.60,25.11, 23.56, 21.17,19.99,19.24, 17.51, 14.86, 13.85,13.35, 12.67 Example 247. Ac

H  967 205.6, 184.5, 177.7, 167.6,153.8, 150.2, 147.9, 146.6,139.1,131.7, 131.6, 111.5,102.6, 79.1, 76.5, 74.4, 72.8,70.1, 69.2, 66.1,62.8, 62.5,59.6, 50.4, 45.9, 40.3, 38.5,31.6, 28.7, 25.1, 23.5,22.6,21.2, 19.9, 19.2, 17.5, 14.9,14.1, 13.8, 13.4, 12.7, Example 248.Ac

H  855 205.4, 184.3, 176.7, 167.5,153.6, 151.5, 151.0, 147.8,138.8,130.3, 127.6, 111.5,107.8, 102.7, 79.0, 76.4, 74.3,72.9, 70.1, 69.4,65.8, 62.8,62.4, 50.3, 45.9, 40.1, 38.4,31.5, 28.2, 25.1, 23.5,22.5,21.1, 19.9, 19.2, 17.5, 14.8,14.0, 13.8, 13.7, 13.3, 12.6, Example249. Ac

H  909 205.6, 184.5, 177.6, 167.6,153.9, 150.2, 147.9, 139.1,132.5,128.4, 112.4, 105.8,102.6, 79.1, 78.9, 76.5, 75.4,74.4, 72.7, 70.1,69.2, 66.1,62.8, 62.5, 50.4, 45.9, 40.2,38.5, 31.6, 28.8, 25.1,23.5,22.6, 21.2, 20.0, 19.2, 17.5,14.8, 14.1, 13.9, 13.3, 12.7, Example250. Ac

H  867 205.6, 184.5, 177.7, 167.5,153.7, 150.8, 147.9, 139.9,139.0,131.0, 126.4, 124.3,122.8, 113.4, 111.8, 102.3,79.1, 76.5, 74.4, 72.9,69.9,68.9, 66.3, 62.8, 62.5, 50.4,45.8, 40.3, 38.5, 31.6, 29.3,25.1,23.5, 22.6, 21.1, 20.0,19.2, 17.5, 14.8, 14.1, 13.9,13.3, 12.7, Example251. Ac

H  866 205.6, 184.5, 177.6, 167.6,154.0, 149.5, 148.2, 143.5,139.3,133.1, 132.1, 113.1,112.5, 102.3, 94.4, 79.1, 76.5,74.5, 72.6, 69.9,68.9, 66.3,62.8, 62.5, 50.4, 45.9, 40.3,38.5, 31.6, 29.3, 25.1,23.5,22.6, 21.1, 19.9, 19.2, 17.5,14.8, 13.9, 13.3, 12.7, Example 252.Ac

H  842 205.7, 184.7, 177.9, 167.9,159.4, 155.8, 154.6, 143.8,129.4,128.5, 108.8, 103.1,79.3, 79.2, 76.8, 74.7, 70.7,70.5, 69.7, 66.2, 63.0,62.7,60.6, 50.7, 46.3, 40.5, 38.7,28.7, 25.4, 23.8, 21.5, 21.3,20.2,19.5, 17.8, 15.1, 14.5,14.1, 13.7, 13.1. Example 253. Ac

H  912 205.8, 184.7, 178.0, 168.3,167.9, 157.5, 154.1, 149.3,148.2,140.9, 139.6, 132.0,112.3, 103.1, 79.3, 76.8, 74.7,73.1, 70.5, 69.7,66.1, 63.1,62.8, 54.0, 50.7, 46.3, 41.0,40.5, 38.8, 34.9, 29.5,28.5,25.4, 23.8, 21.5, 20.3, 19.5,17.8, 15.1, 14.1, 13.7, 13.0. Example254. Ac

H 1003 205.85, 184.53, 177.72,167.64, 153.73, 150.67,148.09, 147.87,138.99,138.83, 137.85, 131.16,130.27, 128.38, 124.57,112.18, 111.95,104.81,102.08, 79.16, 78.7876.48,76.24, 74.51, 72.90, 71.97,67.71,62.76, 62.48, 59.22,52.00, 50.40, 45.82, 38.50,34.91, 25.12, 23.55,20.97,20.69, 19.89, 19.15, 17.56,14.87, 13.74, 13.71, 13.21,12.69Example 255. Ac

H  923 205.84, 184.52, 177.73,167.64, 153.70, 150.81,148.92, 147.86,138.93,136.20, 130.95, 128.25,127.46, 125.20, 124.60,111.98, 105.28, 10208, 79.15,78.77, 76.48, 76.22, 74.50,72.93, 71.98, 67.71, 62.76,62.47,59.30, 51.91, 50.39,45.81, 38.50, 34.93, 25.12,23.54, 20.97, 19.88,19.15,17.56, 14.86, 13.73, 13.21,12.68 Example 256. Ac

H  868 Selected data:206.1, 184.9, 177.9, 167.7,153.9, 143.5, 142.1,141.7,137.0, 111.3, 102.0. Example 257. H

H  772 205.2, 169.5, 154.0, 140.4,136.5, 134.3, 123.0, 121.1,120.9,109.9, 103.4, 80.4, 78.8,78.3, 76.6, 75.9, 70.5, 69.7,66.1, 64.9, 63.1,51.6, 47.8,41.2, 40.5, 38.3, 35.3, 28.5,23.0, 21.4, 21.2, 19.9,17.4,15.7, 14.4, 14.1, 11.9. Example 258. Ac

H  814 205.9, 184.8, 178.0, 167.9,153.7, 140.4, 137.3, 134.8,122.9,121.5, 120.8, 109.1,102.9, 79.4, 79.2, 76.8, 76.3,74.9, 70.4, 69.6,66.2, 63.1,63.0, 50.8, 46.2, 40.5, 38.8,28.9, 25.4, 23.8, 21.4,20.3,19.6, 17.9, 15.2, 14.2, 13.7,12.9. Example 259. Ac

H  857 205.7, 184.7, 178.0, 167.9,154.9, 142.4, 140.1, 133.6,133.1,127.2, 119.7, 107.5,103.1, 79.3, 76.8, 74.7, 72.0,70.5, 69.8, 66.1,63.0, 62.7,19.5, 17.8, 15.1, 14.0, 13.7,13.0. Example 260. Ac

H  859 N/A Example 261. —COCH₂CH₃

H  855 205.5, 187.7, 178.1, 167.5,153.8, 151.1, 147.9, 141.9,139.0,131.1, 127.0, 111.9,107.6, 102.9, 79.1, 76.5, 74.3,72.9, 70.2, 69.5,65.8, 62.8,62.5, 50.4, 46.0, 40.2, 38.6,31.6, 31.0, 28.2, 23.5,22.6,21.2, 20.1, 19.2, 17.5, 14.9,14.1, 13.8, 13.4, 12.7, 8.6 Example262. Ac

H  846 N/A Example 263. Ac

H  859 205.50, 184.42, 177.59,170.17, 167.61, 154.15,153.29, 149.42,147.88,135.95, 135.78, 120.77,102.71, 79.07, 78.93, 76.47,74.43, 72.79,70.14, 69.34,65.87, 62.73, 62.50, 50.39,45.98, 40.17, 38.45,29.64,28.43, 25.08, 23.53, 21.16,19.93, 19.21, 17.49, 14.79,13.78,13.37, 12.71

Example compounds 264–338 of formula A2:

-   -   wherein Ar₁, Ar₂, M, Q, and Z are as delineated for each example        in Table A2.

Example compounds 264–338, where Z═H, are made from the title compoundof Example 3 and the appropriate hydroxylamine of formulaAr₂—M—Ar₁—O—NH₂ via the method delineated in Example 4.

Example compounds 264–338, where Z═F, are made from the title compoundof Example 46 and the appropriate hydroxylamine of formulaAr₂—M—Ar₁—O—NH₂ via the method delineated in Example 4.

The Examples described in Table A2 are single isomers of the Edesignation, which are separated from the E/Z mixture via silicachromatography or HPLC.

The substituted hydroxylamines used in the following examples are eithercommercially available or can be made from readily-available startingmaterials via synthetic methods well known by one of ordinary skill inthe art.

TABLE A2. MS (ESI): ¹³C NMR (125 MHz, Example Q —Ar₁—M—Ar₂ Z m/z (M +H)⁺ CDCl₃): δ Example 264. Ac

H 857 205.7, 184.6, 176.6,167.7, 153.9, 152.8, 149.7,145.2, 142.5,136.8, 127.8,124.4, 122.0, 118.5, 102.5, Example 265. Ac

H 857 N/A Example 266. Ac

H 858 N/A Example 267. Ac

H 780 N/A Example 268. Ac

H 871 205.7, 184.5, 176.2, 169.5,155.7, 153.0, 149.7, 148.6,144.0,136.7, 126.1, 124.4,121.9, 118.9, 102.2, 79.7,79.1, 78.7, 76.2, 75.8,71.5,70.2, 69.2, 66.7, 59.0, 50.8,45.3, 40.6, 39.1, 29.9, 25.6,23.4,21.5, 20.3, 19.8, 17.1,15.8, 14.6, 12.7, 11.9. Example 269. Ac

H 871 205.9, 184.7, 177.2, 169.0,155.5, 153.0, 149.7, 149.0,143.9,136.8, 125.9, 124.4,121.9, 118.8, 102.4, 79.4,79.1, 77.7, 76.3, 70.3,70.0,69.4, 66.4, 58.0, 50.8, 45.1,40.6, 39.0, 29.9, 25.4, 23.4,21.9,21.5, 20.4, 19.7, 17.3,15.5, 14.5, 12.8, 12.1. Example 270. Ac

H 823 206.1, 184.6, 176.5, 169.3,164.0, 157.0, 146.2, 137.4,129.9,127.3, 102.5, 79.7,79.0, 76.2, 75.2, 70.7, 70.5,70.3, 69.8, 66.1, 58.4,54.0,50.9, 45.4, 40.5, 39.0, 36.8,32.0, 29.5, 28.5, 25.5, 23.3,21.6,20.1, 19.7, 17.2, 15.7,14.4, 12.9, 12.0 Example 271. Ac

H 774 205.9, 184.6, 176.7, 169.3,155.9, 137.9, 128.6, 128.5,128.0,102.5, 79.6, 79.0,76.6, 76.2, 75.4, 70.4, 66.2,58.4, 50.9, 45.3, 40.5,39.0,28.7, 25.5, 23.4, 21.5, 20.2,19.7, 17.2, 15.6, 14.4, 12.8,12.0.Example 272. Ac

F 843 204.6, 184.0, 165.8, 157.1,149.6, 146.2, 136.5, 136.3,128.4,128.2, 127.1, 126.8,121.1, 104.0, 80.0, 79.2,79.1, 74.4, 72.8, 70.6,69.9,68.2, 66.1, 57.0, 41.2, 40.5,39.5, 28.4, 25.3, 24.4, 22.8,21.8,21.5, 21.0, 17.3, 15.2,14.1, 11.8. Example 273. Ac

H 857 205.8, 201.1, 184.6, 176.5,169.4, 156.4, 154.5, 150.1,149.7,139.8, 138.1, 136.8,128.5, 125.3, 123.4, 121.8,102.6, 79.7, 79.0,77.8,76.2, 75.4, 70.8, 70.5, 70.2,69.7, 66.1, 58.6, 50.9, 45.4,40.5,39.5, 39.0, 36.8, 28.5,25.5, 23.4, 21.6, 20.2, 19.8,17.2, 15.7, 14.5,12.9, 12.0. Example 274. Ac

F 876 Selected data:204.4(d), 184.0, 165.6,161.8, 157.4, 157.1,145.1,143.5, 128.9, 128.4, 103.7. Example 275. Ac

F 876 (204.4, 204.2), 183.8,176.4, (165.6, 165.4),157.1, 148.7, 144.0,143.9,142.2, 141.4, 140.5, 128.3,125.7, 103.7, (99.4, 97.8),80.3, 79.6,79.0, 75.9, 74.1,70.6, 70.4, 69.6, 67.9, 65.8,56.2, 53.8, 41.0, 40.2,39.0,29.7, 29.3, 28.2, 25.1,(24.1, 23.9), 22.6, 21.3,21.2, 20.7, 17.0,14.9, 14.0,11.6. Example 276. Ac

H 914 206.1, 184.7, 176.5, 169.3,156.3, 151.1, 151.0, 144.8,142.6,139.2, 128.2, 124.6,114.8, 111.9, 102.0, 79.6,79.1, 76.2, 75.6, 71.1,70.6,70.1, 69.0, 66.9, 58.5, 50.9,45.2, 40.6, 39.1, 29.9, 25.5,25.1,23.4, 21.4, 20.2, 19.7,17.2, 15.7, 14.6, 12.8, 12.0. Example 277. Ac

H 913 205.7, 184.3, 176.2, 169.1,161.8, 156.6, 145.0, 138.1,128.7,128.66, 127.9, 127.6,127.1, 102.3, 79.4, 78.8,76.0, 75.0, 70.5, 70.2,70.1,69.4, 65.9, 58.1, 50.7, 45.1,44.0, 40.2, 39.4, 38.8, 36.6,29.7,28.4, 25.2, 23.1, 21.3,19.9, 19.4, 17.0, 15.4, 14.2,12.6, 11.7 Example278. Ac

H 817 N/A Example 279. Ac

F 835 204.8, 184.1, 169.5, 165.8165.7, 157.4, 142,3, 132.7,128.4, 128.3,127.6, 104.0,79.3, 75.7, 70.6, 69.8,66.1, 56.4, 41.2, 40.5,28.5, 25.4,22.8, 21.5,20.9, 17.3, 15.2, 14.2,11.9 Example 280. Ac

H 900 205.8, 184.5, 176.4, 169.3,160.2, 156.9, 151.6, 148.1,147.1,138.7, 138.6, 129.2,127.7, 120.1, 114.1, 102.6,79.7, 79.0, 76.2, 75.3,70.6,70.5, 70.4, 69.7, 66.1, 58.3,50.9, 45.4, 41.2, 40.5, 39.6,39.0,36.7, 28.5, 25.5, 21.6,20.1, 19.7, 17.2, 15.7, 14.4,12.9, 12.0. Example281. Ac

H 899 N/A Example 282. Ac

H 808 205.6, 184.3, 183.0, 176.0,169.1, 156.9, 151.2, 143.6,136.2,127.5, 102.3, 79.5,78.7, 75.9, 75.1, 70.5, 70.2,69.5, 65.9, 58.1, 50.6,45.2,40.2, 38.8, 28.3, 25.3, 23.1,21.3, 19.8, 19.4, 16.9, 15.4,14.2,12.7, 11.7 Example 283. Ac

H 893 Selected data:206.0, 184.6, 176.3, 169.4,165.9, 156.6, 142.2,138.3,134.5, 129.3, 128.5, 127.3,124.7, 120.4, 102.5, 79.7,79.1. Example284. Ac

H 808 Selected data:205.9, 185.9, 174.7, 170.0,158.7, 151.0, 145.7,102.5,98.8. Example 285. Ac

H 831 205.9, 184.6, 177.5, 169.3,168.4, 156.5, 141.6, 134.1,128.3,127.0, 102.7, 79.7,76.2, 75.8, 70.5, 69.8,66.1, 58.4, 50.9, 45.4,40.5,39.7, 39.0, 28.5,28.5, 27.1, 25.5, 23.4,21.6, 20.2, 19.7, 17.2,15.6,14.4, 13.0, 12.0, Example 286. Ac

H 845 205.9, 184.6, 176.5, 169.3,167.6, 156.4, 141.5, 134.3,128.3,127.0, 102.6, 79.7,79.0, 76.2, 75.4,70.5, 69.7, 66.1, 58.4,50.9, 45.4,40.5, 39.6,39.0, 36.8, 35.1, 28.5,25.5, 23.4, 21.6, 20.2,19.7, 17.2,15.6, 15.2,14.4, 13.0, 12.0 Example 287. Ac

H 832 204.6, 183.5, 176.7, 166.6,166.0, 152.6, 142.3, 128.5,128.2,126.4, 101.8, 78.1,78.0, 75.5, 74.2, 73.4,69.2, 68.5, 64.8, 61.8,61.7,51.0, 49.5, 45.0,39.2, 37.5, 27.3, 24.1,22.6, 20.2, 19.0, 18.3,16.5,13.9, 12.8, 12.4,11.6, Example 288. Ac

H 857 205.9, 184.6, 176.5, 169.3,169.0, 156.5, 141.7, 133.9,128.3,127.0, 102.6, 79.7,79.0, 76.2, 75.7, 75.4,70.5, 69.7, 66.1, 58.4,50.9,45.4, 40.5, 39.0,28.5, 25.5, 23.4, 21.6,20.2, 19.7, 17.2, 15.6,14.4,13.0, 12.0, 7.0 Example 289. Ac

H 916 205.9, 184.8, 178.1, 167.7,153.7, 149.3, 148.9, 145.3,139.2,128.03, 127.95,122.0, 118.6, 111.7, 109.6,102.8, 79.4, 79.1, 76.8,74.5,71.0, 70.3, 69.4, 66.4,63.1, 62.9, 56.21, 56.19,50.8, 46.1, 40.5, 38.8,29.9,29.2, 25.4, 23.8, 21.4, 20.3,19.5, 17.8, 15.1, 14.2, 13.6,13.0.Example 290. Ac

H 862 205.9, 184.5, 176.5, 169.3,167.4, 156.7, 156.3, 132.1,130.3,128.8, 122.2, 110.8,102.5, 79.6, 78.9, 77.6,76.2, 75.3, 71.0, 70.6,70.4,69.7, 66.1, 58.6, 55.7, 52.3,50.8, 45.4, 40.4, 39.6, 39.0,29.5,28.5, 25.4, 22.3, 21.5,20.2, 19.7, 17.2, 15.6, 14.4,12.9, 11.9 Example291. Ac

H 831 Selected data:205.9, 184.6, 176.6, 169.3,168.4, 155.9, 137.7,133.8,129.5, 119.8, 102.4. Example 292. Ac

H 805 205.6, 184.3, 175.9, 169.1,157.2, 148.4, 137.1, 126.7,114.4,109.7, 102.3, 79.5,78.7, 75.9, 75.0, 70.2, 69.9,69.5, 58.1, 50.6, 45.2,40.2,38.8, 28.2, 25.3, 23.1, 21.3,19.8, 19.4, 16.9, 15.4, 14.1,12.7,11.7 Example 293. Ac

H 858 205.8, 184.6, 176.5, 169.3,156.5, 148.9, 144.3, 144.2,142.5,141.7, 140.8, 128.5,125.9, 102.6, 79.7, 79.0,77.6, 76.2, 75.4, 70.8,70.6,70.5, 69.7, 66.1, 58.4, 50.8,45.3, 40.5, 39.6, 39.0, 36.8,28.5,25.5, 23.4, 21.6, 20.2,19.7, 17.2, 15.7, 14.4, 12.9,12.0. Example 294.Ac

H 847 205.8, 184.6, 176.7, 169.3,155.9, 137.7, 133.0, 129.6,118.7,102.6, 79.6, 79.0,76.2, 76.1, 75.4, 70.5(2),69.6, 66.2, 58.4, 52.6,50.9,45.3, 40.5, 39.6, 39.0, 36.9,29.9, 28.7, 25.5, 23.4, 21.6,20.3,19.7, 17.2, 15.6, 14.5,12.9, 12.0. Example 295. Ac

F 890 N/A Example 296. Ac

H 832 205.9, 184.6, 176.4, 169.3,168.8, 167.9, 156.6, 153.9,142.3,132.0, 128.4, 128.1,127.1, 102.6, 79.7, 79.0,76.2, 75.6, 70.5,69.7,66.1, 58.5, 50.9, 45.4,40.5, 39.0, 28.5, 25.5,23.4, 21.6, 20.1,19.7,17.2, 15.7, 14.4, 13.0,12.0 Example 297. Ac

H 876 N/A Example 298. Ac

H 801 N/A Example 299. Ac

H 872 N/A Example 300. H

H 872 205.6, 189.1, 170.0, 169.2,157.5, 151.1, 151.0, 144.8,142.8,139.2, 127.9, 124.5,114.7, 112.1, 102.3, 80.6,80.3, 78.8, 76.9, 76.0,71.9,71.2, 70.4, 69.5, 66.1, 60.2,50.7, 45.7, 41.6, 40.4, 39.5,35.3,28.9, 25.0, 23.2, 21.6,20.0, 19.7, 16.9, 14.8, 14.6,12.9, 11.9. Example301. Ac

H 851 N/A Example 302. Ac

H 887 205.9, 184.6, 176.6, 169.3,163.7, 156.1, 150.3, 145.8,141.8,139.2, 128.4, 124.2,111.4, 109.1, 102.3, 79.6,79.1, 76.2, 75.5, 71.1,70.6,70.3, 69.3, 66.5, 58.4, 53.6,50.9, 45.2, 40.6, 39.0, 30.0,25.5,23.4, 21.5, 20.3, 19.7,17.2, 15.7, 14.5, 12.8, 12.0. Example 303. H

H 830 205.5, 188.1, 170.0, 158.3,157.5, 151.2, 145.9, 141.7,138.4,127.9, 124.0, 109.4,107.1, 102.4, 80.6, 80.3,78.7, 77.1, 76.0, 71.9,71.2,70.5, 69.7, 66.1, 60.4, 50.7,45.7, 42.0, 40.5, 39.5, 35.3,29.9,28.6, 23.2, 21.6, 20.1,19.7, 16.9, 14.8, 14.6, 12.9,11.9. Example 304. H

F 848 N/A Example 305. Ac

H 857 N/A Example 306. Ac

H 852 205.8, 184.6, 176.7, 169.3,164.9, 157.4, 156.1, 140.7,137.2,128.6, 128.4, 119.2,102.6, 79.6, 79.0, 76.2,75.4, 70.5, 69.7, 66.1,58.4,50.9, 45.4, 40.5,39.0, 28.5, 25.5, 25.5,23.4, 21.6, 20.3, 19.7,15.6,14.5, 12.9, 12.0 Example 307. Ac

H 882 205.8, 184.7, 178.1, 167.8,154.5, 154.2, 145.0, 142.6,137.7,133.8, 127.9, 126.41,126.37, 122.1, 117.4, 103.0,79.4, 79.2, 76.8, 74.6,70.9,70.5, 69.7, 66.2, 63.1, 62.9,50.7, 46.2, 40.5, 38.8, 28.7,25.4,23.9, 21.5, 20.3, 19.5,17.8, 15.1, 14.1, 13.7, 13.0. Example 308. Ac

H 853 205.6, 184.3, 176.1, 169.1,156.6, 153.5, 151.2, 149.3,144.3,143.5, 143.4, 137.2,134.3, 121.1, 102.4, 79.5,79.7, 76.0, 75.2,73.4,70.2, 69.5, 65.9, 58.2,50.6, 45.2, 40.2, 38.8,28.3, 25.3, 23.1,21.3,19.9, 19.5, 17.0, 15.4,14.2, 12.8, 11.7 Example 309. Ac

H 852 205.8, 184.5, 176.5, 169.3,156.6, 156.4, 155.9, 149.3,137.5,137.1, 133.5, 123.8,121.4, 121.0, 102.7, 79.7,79.0, 76.2, 75.4,73.8,70.5, 69.8, 66.1, 58.4,50.9, 45.4, 40.5, 39.0,28.5, 25.5, 23.4,21.6,20.2, 19.7, 17.2, 15.7,14.4, 13.0, 12.0 Example 310. Ac

H 858 205.8, 184.6, 176.4, 169.4,156.9, 151.0, 149.4, 144.2,137.6,134.7, 121.5, 119.6,102.7, 79.7, 79.0, 76.2,75.5, 73.6, 70.5, 70.4,69.7,66.1, 58.4, 50.9, 45.5, 40.5,39.0, 36.8, 30.0, 28.5, 25.6,23.4,21.6, 20.2, 19.7, 17.2,15.7, 14.4, 13.0, 12.0. Example 311. Ac

H 790 205.8, 184.5, 176.6, 169.3,158.5, 155.9, 148.8, 139.4,123.2,108.6, 102.7, 79.6,79.0, 76.2, 75.4, 74.0, 70.5,69.7, 66.1, 58.4, 50.8,45.4,40.5, 39.6, 39.0, 36.8, 28.5,25.5, 23.4, 21.6, 20.3, 19.7,17.2,15.6, 14.4, 12.9, 12.0. Example 312. Ac

H 863 205.6, 184.3, 176.1, 169.0,162.0, 156.1, 143.2, 142.6,137.6,127.7, 126.1, 118.0,101.8, 79.3, 78.8, 75.9,75.4, 70.4, 70.4, 69.9,68.8,66.5, 58.2, 50.6, 44.9, 40.3,38.8, 36.5, 29.6, 25.2, 23.1,21.1,19.9, 19.4, 16.9, 15.4,14.3, 12.5, 11.7. Example 313. Ac

F 859 204.8, 204.5, 184.0, 176.3,165.8, 165.6, 157.4, 151.4,148.2,142.1, 139.8, 131.1,127.3, 112.3, 107.8, 104.0,99.6, 98.0, 79.9, 79.3,76.1,73.9, 73.4, 70.6, 69.9, 67.9,66.0, 56.2, 41.2, 40.5, 39.2,37.7,31.2, 29.9, 28.4, 25.3,24.5, 24.4, 22.8, 21.6, 21.5,21.0, 17.3, 15.2,14.2, 11.9 Example 314. Ac

H 841 205.8, 184.5, 176.4, 169.3,156.7, 151.4, 148.1, 142.1,139.6,131.3, 127.3, 112.3,107.9, 102.6, 79.7, 79.0,76.2, 75.4, 73.4, 70.5,70.3,69.7, 66.1, 58.3, 50.9, 45.4,40.5, 39.7, 39.0, 36.8, 28.5,25.5,23.3, 21.6, 20.2, 19.7,17.2, 15.6, 14.4, 13.0, 12.0. Example 315. Ac

H 901 N/A Example 316. Ac

F 808 204.6, 204.4, 184.0, 176.7,165.8, 165.6, 158.4, 156.8,148.9,139.5, 123.1, 108.5,104.1, 99.6, 98.0, 79.9,79.3, 76.1, 74.0, 70.6,69.9,68.0, 66.0, 56.3, 41.2, 40.5,39.2, 37.8, 31.2, 29.9, 28.4,25.3,24.5, 24.3, 22.8, 21.6,21.5, 20.9, 17.3, 15.2, 14.2,11.9. Example 317.Ac

H 858 205.9, 184.6, 175.5, 169.3,163.1, 156.3, 139.5, 130.4,130.1,129.2, 127.6, 102.7,79.7, 76.2, 76.0, 70.5,69.7, 66.1, 58.4, 50.9,45.4,40.5, 39.0, 28.5,25.5, 23.4, 21.6, 20.2,19.7, 17.2, 15.7, 14.4,12.0Example 318. Ac

F 876 203.5, 203.3, 182.8, 164.6,164.4, 161.9, 156.0, 138.1,129.1,128.7, 128.0, 126.3,102.8, 98.4, 96.7, 78.0,74.7, 72.8, 69.3, 68.6,66.7,64.8, 55.2, 39.9,39.2, 27.1, 24.1, 23.2,23.0, 21.5, 20.4, 20.2,19.7,16.0, 14.0, 12.9,10.6 Example 319. Ac

H 842 N/A Example 320. Ac

H 841 205.9, 184.5, 176.3, 169.4,157.0, 149.1, 148.8, 139.7,135.2,132.1, 130.8, 116.5,112.2, 102.7, 79.7, 79.0,77.4, 76.2, 75.4, 73.0,70.4,70.3, 69.7, 66.1, 58.4, 50.9,45.5, 40.5, 39.7, 39.0, 36.7,28.5,25.5, 23.3, 21.6, 20.1,19.7, 17.2, 15.6, 14.4, 13.0,12.0. Example 321.Ac

H 873 205.62, 184.33, 176.23,169.06, 167.60, 159.80,156.14, 139.99,130.03,128.60, 126.92, 102.26,79.37, 78.75, 75.93, 75.57,75.15, 70.14,69.34, 67.94,65.91, 58.17, 53.40, 50.61,45.12, 40.20, 39.39,38.76,36.53, 29.66, 28.47, 25.58,25.26, 23.08, 21.27, 19.89,19.41,16.95, 15.40, 14.16,12.68, 11.72 Example 322. Ac

H 867 N/A Example 323. Ac

H 799 N/A Example 324. Ac

H 874 Partial ¹³C NMR205.63, 184.32, 176.04 Example 325. Ac

H 855 205.8, 184.5, 176.4, 169.3,156.6, 151.5, 148.1, 143.1,139.5,130.7, 125.8, 118.5,111.9, 102.6, 79.7, 79.0,76.2, 75.5, 73.5, 70.4,70.3,69.7, 66.2, 58.3, 50.9, 45.4,40.5, 39.7, 39.0, 36.8, 29.5,28.6,25.5, 23.3, 21.6, 20.2,19.7, 17.2, 15.6, 14.4, 13.0,12.0, 9.3. Example326. Ac

H 874 205.71, 184.39, 176.16,171.88, 169.10, 156.24,153.13, 141.02,129.99,128.53, 125.93, 102.14,79.40, 78.82, 75.92, 75.42,75.20, 70.27,70.09, 69.19,66.09, 58.26, 53.41, 50.63,45.13, 40.24, 39.37,38.80,36.50, 28.79, 25.31, 23.09,21.24, 19.87, 19.41, 16.94,21.24,19.87, 19.41, 16.94,15.48, 14.20, 12.68, 11.73 Example 327. Ac

H 858 205.67, 184.31, 176.14,169.08, 168.29, 156.29,151.02, 141.50,128.73,128.13, 102.22, 79.39,78.76, 75.93, 75.42, 75.21,70.11, 69.27,66.07, 58.17,50.64, 45.11, 40.24, 39.39,38.78, 36.55, 28.62,25.28,23.08, 21.26, 19.90, 19.39,16.95, 15.40, 14.18, 12.68,11.72Example 328. Ac

H 842 205.8, 184.4, 169.1, 156.8,148.1, 139.6, 134.1, 121.1,113.5,109.7, 101.8, 79.4,78.8, 75.9, 75.3, 72.8, 69.8,68.7, 66.4, 58.1, 50.7,45.1,40.3, 38.8, 36.4, 31.6, 29.5,25.3, 23.0, 22.6, 21.1, 19.8,19.3,16.9, 15.4, 14.2, 14.1,12.7, 11.7. Example 329. Ac

H 967 205.6, 184.3, 176.1, 169.1,156.5, 150.3, 147.9, 146.5,139.4,131.7(2), 111.6,102.2, 79.4, 78.8, 75.9,73.0, 70.1, 69.2, 66.2,59.6,58.1, 50.7, 45.1, 40.3, 39.4,38.8, 36.5, 31.6, 28.7, 25.3,23.1,21.3, 19.9, 19.4, 16.9,15.4, 14.2, 14.1, 12.7, 11.7, Example 330. Ac

H 855 205.5, 184.2, 176.2, 169.0,156.3, 151.5, 151.1, 147.9,139.2,130.3, 127.7, 111.6,107.8, 102.3, 79.4, 78.7,75.9, 75.2, 73.2, 70.0,69.3,66.0, 58.0, 50.6, 45.1, 40.2,38.7, 31.5, 28.5, 25.2, 23.1,22.6,21.3, 19.9, 19.4, 16.9,15.4, 14.2, 14.0, 13.9, 12.7,11.7, Example 331.Ac

H 909 205.6, 184.3, 176.1, 169.1,156.7, 150.2, 147.9, 139.5,132.4,128.4, 112.5, 105.7,102.3, 79.4, 78.7, 75.9,75.2, 72.9, 70.2, 70.0,69.4,65.9, 58.1, 50.6, 45.2, 40.2,39.4, 38.7, 36.5, 31.6, 28.3,25.3,23.0, 22.6, 21.3, 19.9,19.4, 16.9, 15.4, 14.1, 12.8,11.7, Example 332.Ac

H 867 N/A Example 333. Ac

H 866 N/A Example 334. Ac

H 912 N/A Example 335. Ac

H 1003 205.76, 184.34, 176.04,169.17, 156.45, 150.73,148.04, 147.87,139.38,137.91, 131.05, 130.28,128.41, 124.55, 112.12,112.06, 104.75,101.59,79.31, 78.76, 76.26, 75.91,75.02, 73.11, 71.95, 70.20,67.70,59.27, 58.12, 51.91,58.12, 51.92, 50.57, 45.18,58.12, 51.92, 50.57,45.18,39.41, 38.77, 36.45, 34.93,25.28, 23.06, 21.06, 19.80,19.35,16.95, 15.43, 13.98.12.65, 11.696 Example 336. Ac

H 923 205.75, 184.34, 176.07,169.17, 156.40, 150.90,148.88, 147.90,139.36,136.28, 130.84, 128.30,127.49, 125.17, 124.59,112.10, 105.24,101.61,79.31, 78.77, 76.26, 75.92,75.06, 73.19, 71.96, 70.21,67.71,59.27, 58.13, 51.94,50.59, 45.18, 39.41, 38.78,36.46, 34.95, 25.30,23.08,21.07, 19.82, 19.36, 16.96,15.44, 14.00, 12.66, 11.70 Example 337.H

H 772 205.7, 169.9, 157.5, 140.7,137.3, 134.5, 122.8, 120.8,120.5,108.7, 102.5, 80.7,80.1, 78.9, 76.7, 76.2, 76.0,71.9, 70.5, 69.7, 66.1,60.2,50.7, 45.9, 41.8, 40.5, 39.5,35.5, 28.6, 23.2, 21.6, 20.0,17.0,14.8, 14.5, 13.1, 11.9. Example 338. Ac

H 846 N/A

Example compounds 338–353 of formula B:

-   -   wherein R₁₁, Q, and Z are as delineated for each example in        Table B.

Example compounds 338–353, where Z═H, are made from the title compoundof formula (1-5), wherein V═N—Ac, R₁₁═H, and R₂′═H, and the appropriatebromo compound of formula Br—R₁₁, wherein R₁₁ is previously defined, viaessentially the same synthetic route described in Example 35.

Example compounds 338–353, where Z═F, are made from the compound ofExample 46, Step 46a and the appropriate bromo precursor via the methoddelineated in Example 35.

The Examples described in Table B comprise mixtures of E and Z isomers,which can be separated via silica chromatography or HPLC.

The bromo compounds used to form the following examples are commerciallyavailable or can be made from readily-available starting materials viasynthetic methods well known by one of ordinary skill in the art.

TABLE B MS (ESI): ¹³C NMR (125 MHz, Examples Q —R₁₁ Z m/z (M + H)⁺CDCl₃): δ Example 339. H H H 625 N/A Example 340. OMOM H H 685 N/AExample 341. OMOM

H 761 N/A Example 342. Ac

H 819 N/A Example 343. Ac

H 819 N/A Example 344. Ac

H 835 N/A Example 345. Ac

H 769 N/A Example 346. Propionyl

H 783.36 N/A Example 347. Ac

H 803 N/A Example 348. C(O)OMe

H 785 N/A Example 349. C(O)NH₂ H H 668 N/A Example 350. Me H H 639 N/AExample 351. BOM H H 762 N/A Example 352. Ac

H 739 N/A Example 353. Ac

H 692 N/A

Example compounds 354–375 of formula B1:

-   -   wherein R₁₁, Q, and Z are as delineated for each example in        Table B1.

Example compounds 354–375, where Z═H, are made from the title compoundof formula (1-5), wherein V═N—Ac, R₁₁═H, and R₂′═H, and the appropriatebromo compound of formula Br—R₁₁, wherein R₁₁ is as previously defined,via essentially the same synthetic route described in Example 35.

Example compounds 354–375, where Z═F, are made from the compound ofExample 46, Step 46a and the appropriate bromo precursor via the methoddelineated in Example 35.

The Examples described in Table B1 are single isomers of the Edesignation, which are separated from the E/Z mixture via silicachromatography or HPLC.

The bromo compounds used to form the following examples are commerciallyavailable or can be made from readily-available starting materials viasynthetic methods well known by one of ordinary skill in the art.

TABLE B1 MS (ESI): ¹³C NMR (125 MHz, Examples Q —R₁₁ Z m/z (M + H)⁺CDCl₃): δ Example 354. Ac

H 768 N/A Example 355. Ac

H 768 N/A Example 356. Ac

H 783 206.2, 184.4, 177.7, 167.8,157.4, 151.5, 144.3, 140.4,117.9,110.1, 107.9, 103.0,93.3, 86.9, 79.5, 78.4, 76.2,72.7, 70.2, 69.3, 68.2,66.1,65.8, 50.8, 46.6, 40.3, 38.5,25.1, 23.8, 21.2, 19.5, 17.3,15.1,13.8, 12.9, Example 357. Ac

H 782 206.2, 184.4, 177.8, 167.7,146.6, 143.4, 133.0, 118.4,114.6,112.9, 103.0, 96.8,84.4, 79.6, 78.3, 76.2, 72.6,70.2, 69.3, 68.3, 66.1,65.8,50.8, 46.6, 40.3, 38.5, 25.1,23.7, 21.2, 19.5, 17.3, 15.1,13.8,12.7, Example 358. Ac

H 797 N/A Example 359. Ac

H 835 N/A Example 360. Ac

F 787 205.36 (d), 183.93, 164.92(d),137.25, 136.54, 136.08,134.26,128.52, 128.17,126.87, 123.95, 103.95,80.17, 79.96, 75.93, 71.71,70.37,69.51, 66.33, 65.99,65.82, 40.65, 40.20, 38.90,37.24, 28.27, 25.08,24.68,24.50, 23.07, 21.18, 21.06,17.11, 15.05, 14.14, 12.57 Example 361.Ac

H 771 205.72, 169.32, 169.60,137.16, 135.90, 128.53,128.25, 127.86,126.71,123.91, 103.75, 80.62, 78.92,76.88, 70.41, 70.30, 69.30,66.16,65.56, 59.83, 53.76,51.63, 48.93, 40.27, 29.23,28.69, 23.57, 23.14,21.45,21.16, 16.62, 14.34, 12.61 Example 362. Ac

H 827 206.2, 184.4, 177.6, 167.6,152.5, 149.5, 145.6, 140.7,136.5,132.2, 131.1, 129.4,124.6, 121.8, 118.8, 103.1,79.3, 78.6, 76.2, 75.0,73.0,70.3, 69.4, 67.7, 67.1, 66.2,65.9, 50.9, 46.9, 40.2, 38.6,29.7,28.4: 25.1: 23.8, 21.2,20.5, 19.7, 17.4, 14.9, 14.2,13.8, 12.1. Example363. Ac

H 805 Selected:206.3, 184.7, 177.9, 167.8,163.3, 161.4, 159.6,136.2,135.2. 128.7, 127.7, 126.3,111.8, 111.6, 103.4, 79.7,78.7, 76.4,72.5, 70.5, 69.7,66.1, 51.1, 47.2, 40.5, 38.8,29.5, 28.6, 25.4, 23.9,21.5,19.9, 17.7, 15.1, 14.1, 13.1. Example 364. 2-methoxyacetyl

H 799 206.4, 183.9, 182.0, 167.8,137.6, 136.3, 134.2, 128.7,128.6,128.0, 127.1, 127.0,124.1, 103.4, 79.8, 78.7,77.5, 76.5, 73.5, 72.7,70.5,69.7, 66.7, 66.1, 59.7, 51.1,40.5, 39.0, 28.5, 23.9, 21.5,20.9,19.9, 17.7, 15.2, 14.2,13.1. Example 365. 2-O-acyl-acetyl

H 827 N/A Example 366. 2-Fmoc-acetyl

H 1006 N/A Example 367. Ac

H 787 206.3, 184.7, 178.0, 167.8,(161.7, 159.7), 136.4, 135.1,(129.1,129.06), 128.7,128.0, 126.7, 126.65, (125.5,125.4), 124.2, (116.1,116.0),103.5, 79.7, 78.7, 76.4, 72.5,70.6, 69.8, 66.7, 66.5, 66.1,51.1,47.2, 40.5, 38.8, 31.2,28.5, 25.4, 23.9, 21.5, 20.8,20.0, 17.7, 15.1,14.5, 14.1,13.0. Example 368. Ac

H 783 N/A Example 369. 2-hydroxyacetyl

H 785 N/A Example 370. 2-aminoacetyl

H 784 N/A Example 371. Ac

H 814 206.1, 184.4, 177.5, 167.7,146.8, 143.8, 137.6, 135.0,133.4,130.1, 128.1, 127.0,124.0, 123.4, 103.2, 79.4,78.6, 76.2, 72.3, 70.3,69.5,66.4, 66.0, 65.8, 50.8, 47.0,40.2, 38.5, 28.2, 25.1, 23.7,21.2,19.7, 17.5, 14.8, 13.8,13.0 Example 372. Ac

H 821 Partial ¹³C NMR: 206.09,184.41, 167.60, 158.43 Example 373. Ac

H 799 206.10, 184.38, 167.47,159.30, 136.23, 135.69,132.65, 130.18,127.96,121.79, 113.88, 103.16,79.58, 78.31, 76.16, 72.09,70.27, 69.46,66.53, 66.43,65.80, 55.19, 50.82, 46.87,40.19, 38.57, 31.63,28.20,25.22, 25.08, 23.68, 22.60,21.22, 20.51, 19.67, 17.43,14.87,14.08, 13.80, 12.89 Example 374. Ac

H 803 Selected:206.4, 184.7, 177.9, 167.8,139.5, 135.7, 135.5,134.8,134.7, 129.9, 127.8, 126.8,125.4, 125.3, 103.4, 79.8,78.7, 76.5,72.5, 70.5, 69.7,66.8, 66.4, 66.1, 54.0, 51.1,47.2, 40.5, 38.8, 31.2,29.5,28.5, 25.4, 23.9, 21.5, 19.9,17.8, 15.1, 14.1, 13.2. Example 375.Ac

H 800 N/A

Example compounds 376–384 of formula B2:

-   -   wherein R₁₁, Q, and Z are as delineated for each example in        Table B2.

Example compounds 376–384, where Z═H, are made from the title compoundof formula (1-5), wherein V═N—Ac, R₁₁═H, and R₂′═H, and the appropriatebromo compound of formula Br—R₁₁, wherein R₁₁ is as previously defined,via essentially the same synthetic route described in Example 35.

Example compounds 376–384, where Z═F, are made from the compound ofExample 46, Step 46a and the appropriate precursor via the methoddelineated in Example 35.

The Examples described in Table B2 are single isomers of the Zdesignation, which are separated from the E/Z mixture via silicachromatography or HPLC.

The bromo compounds used to form the following examples are commerciallyavailable or can be made from readily-available starting materials viasynthetic methods well known by one of ordinary skill in the art.

TABLE B2 MS (ESI): ¹³C NMR Examples Q —R₁₁ Z m/z (M + H)⁺ (125 MHz,CDCl₃): δ Example 376. Ac

H 827 205.3, 184.5, 176.0, 168.8, 152.4, 149.4,145.1, 141.0, 136.4,135.2, 129.5, 126.1,124.8, 121.7, 118.7, 102.4, 79.0, 78.6,77.6, 76.3,76.0, 74.8, 70.2, 69.4, 65.8,61.6, 50.3, 45.1, 40.1, 39.2, 36.4,28.2,25.0, 23.2, 21.2, 20.0, 19.9, 16.9, 15.5,14.0, 12.5, 11.9. Example377. Ac

H 767 205.33, 184.75, 177.42, 168.32, 146.16,131.61, 128.18, 128.12,123.39, 115.83,102.24, 96.78, 85.24, 78, 87, 78.59, 76.18,75.22, 72.63,70.19, 69.37, 65.94, 61.88,50.45, 44.87, 40.25, 38.71, 25.29,23.31,21.22, 20.00, 19.56, 17.30, 15.34, 14.13,12.65, 12.11 Example 378.Ac

H 768 205.36, 184.66, 177.23, 168.24, 149.87,148.14, 135.89, 127.32,122.58, 114.98,102.54, 95.65, 84.94, 78.86, 78.77, 76.12,75.33, 74.94,72.49, 70.24, 69.94, 69.49,65.83, 63.03, 50.46, 45.13, 40.22,38.67,28.25, 25.29, 23.30, 21.25, 20.03, 19.59,17.27, 15.29, 14.09,12.82, 12.11 Example 379. Ac

H 768 205.23, 184.50, 177.45, 168.08, 152.35,148.40, 147.32, 138.48,122.79, 115.62,102.36, 93.03, 88.40, 78.74, 78.57, 76.18,74.60, 74.51,71.82, 70.19, 69.46, 65.83,61.75, 50.33, 44.98, 40.20, 39.90,38.71,28.27, 25.22, 23.32, 21.23, 19.85, 19.36,17.38, 15.20, 13.98,12.74, 12.20 Example 380. Ac

H 797 205.33, 194.80, 177.48, 168.27, 159.56,145.23, 133.06, 132.98,116.10, 115.59,113.93, 113.77, 102, 30, 96, 86, 84.07,78.88, 78.53,76.16, 75.16, 72.70, 70.21,69.43, 65.84, 61.87, 55.25, 50.42,44.84,40.22, 38.69, 30.91, 28.33, 25.28, 23.31,21.26, 20.00, 19.57,17.30, 15.33, 14.13,12.63, 12.12 Example 381. Ac

H 784 In CD₃OD211.7, 207.1, 187.1, 180.0, 170.0, 160.1,151.4, 147.1,141.7, 116.6, 109.6, 103.5,95.4, 86.6, 80.1, 77.6, 76.4, 72.5,72.0,70.6, 70.2, 65.9, 62.5, 56.0, 46.1, 40.8,40.2, 32.2, 32.1, 29.5,25.4, 24.5, 21.5,20.3, 20.2, 18.4, 15.6, 14.5, 12.6 Example 382. Ac

H 782 205.3, 184.9, 177.5, 168.4, 144.5, 133.0,130.9, 128.8, 116.2,114.6, 102.3, 97.8,83.4, 78.9, 78.5, 76.2, 73.0, 70.2, 69.4,65.9, 61.9,50.4, 44.8, 40.2, 38.7, 31.6,28.4, 25.3, 23.3, 21.3, 20.0, 19.6,17.3,15.4, 14.1, 12.6, 12.1 Example 383. Ac

H 835 205.44, 184.55, 177.45, 168.12, 147.55,131.84, 125.02, 115.58,102.35, 95.04,87.57, 78.77, 78.60, 76.18, 74.59, 71.89,70.19, 69.48,65.85, 61.76, 50.41, 44.98,40.21, 39.88, 38.71, 28.27, 25.24,23.31,21.21, 19.88, 19.39, 17.37, 15.22, 14.04,12.74, 12.18 Example 384.Ac

H 835 N/A

Example compounds 385–391 of formula C:

-   -   wherein R₁₁, Q, and Z are as delineated for each example in        Table C.

Example compounds 384–390, where Z═H, are made from the title compoundof formula (1-5), wherein V═N—Ac, R₁₁═H, and R₂′═H, and the appropriatecompounds of formula NH₂—R₁₁, NH₂NH₂—SO₂—R₁₁, NH₂NH₂—R₁₁,NH₂NH₂—N═CH—R₁₁, NH₂NH₂—C(O)—R₁₁, where R₁₁ is as previously defined viaessentially the same synthetic route described in Example 4.

Example compounds 384–390, where Z═F, are made from the compound ofExample 46, Step 46a and the appropriate amino precursor via the methoddelineated in Example 4

The Examples described in Table C comprise mixtures of E and Z isomers,which can be separated via silica chromatography or HPLC.

The amino compounds used to form the following examples are commerciallyavailable or can be made from readily-available starting materials viasynthetic methods well known by one of ordinary skill in the art.

MS (ESI): ¹³C NMR (125 MHz, Examples Q —R₁₁ Z m/z (M + H)⁺ CDCl₃): δExample 385. Ac

H 758 N/A Example 386. Ac

H 760 N/A Example 387. Ac

H 772 N/A Example 388. Ac

H 822 N/A Example 389. Ac

H 823 205.6, 185.1, 174.3, 169.8,156.9, 138.6, 32.9, 129.0,128.6, 102.3,80.4, 78.9,78.6, 76.1, 75.3, 73.9, 70.4,69.8, 66.1, 59.9, 50.8,45.6,40.5, 38.9, 36.0, 29.9, 28.5,25.5, 23.1, 21.6, 21.5, 19.9,19.7,17.1, 15.3, 14.3, 12.9,11.8. Example 390. Ac

H 788 N/A Example 391. Ac

H 799 N/A

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

1. A compound represented by formula:

or a pharmaceutically acceptable salt, ester, prodrug, racemic mixtureor stereoisomer thereof.
 2. A compound according to claim 1 wherein thecompound is a pharmaceutically acceptable salt.
 3. A compound accordingto claim 1 wherein the compound is a free base.
 4. A compound accordingto claim 1 wherein the compound is an ester or prodrug.
 5. A compoundaccording to claim 1 wherein the compound is an E oxime isomer.
 6. Acompound according to claim 1 wherein the compound is a Z oxime isomer.7. A method for treating a protozoa infection or bacterial infection ordisorders related to such infections in a subject in need of suchtreatment, comprising administering to said subject a therapeuticallyeffective amount of a compound according to the formula:

and pharmaceutically acceptable salts, esters, prodrugs, racemicmixtures and stereoisomers thereof.
 8. A method according to claim 7wherein the compound is pharmaceutically acceptable salt.
 9. A methodaccording to claim 7 wherein the compound is a free base.
 10. A methodaccording to claim 7 wherein the compound is an ester or prodrug.
 11. Amethod according to claim 7 wherein the compound is an E oxime isomer.12. A method according to claim 7 wherein the compound is a Z oximeisomer.
 13. The method according to claim 7 wherein the compound isadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.14. The method according to claim 7 wherein the compound is administeredorally or by injection.
 15. The method according to claim 7 wherein thesubject is a human.
 16. The method according to claim 7 wherein thecompound is administered in combination with one or more antibiotics.17. The method according to claim 16 wherein the antibiotic is selectedfrom the group consisting of penicillin, amoxicillin, azithromycin,erythromycin, ciproflaxin, telithromycin, and cethromycin or apharmaceutically acceptable salt ester, or prodrug thereof.
 18. Themethod according to claim 7 wherein the infection or disorder isselected from the group consisting of pneumonia, otitis media,sinusitus, bronchitis, tonsillitis, and mastoiditis related to infectionby Streptococcus pneumoniae, Haemophilus influenzae, Moraxellacatarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.Pseudomonas spp.; pharynigitis, rheumatic fever, and glomerulonephritisrelated to infection by Streptococcus pyogenes, Groups C and Gstreptococci, Clostridium diptheriae, or Actinobacillus haemolyticum;respiratory tract infections related to infection by Mycoplasmapneumoniae, Legionella pneumophila, Streptococcus pneumoniae,Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin andsoft tissue infections, abscesses and osteomyelitis, and puerperal feverrelated to infection by Staphylococcus aureus, coagulase-positivestaphylococci, S. pyogenes, S. agalactiae, Streptococcal groups C–F.viridans streptococci, Corynebacterium spp., Clostridium spp., orBartonella henselae; uncomplicated acute urinary tract infectionsrelated to infection by S. saprophyticus or Enterococcus spp.;urethritis and cervicitis; and sexually transmitted diseases related toinfection by Chlamydia trachomatis, Haemophilus ducreyi, Treponemapallidum, Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseasesrelated to infection by S. aureus, or Groups A, S, and C streptococci;ulcers related to infection by Helicobacter pylori; systemic febrilesyndromes related to infection by Borrelia recurrentis; Lyme diseaserelated to infection by Borrelia burgdorferi; conjunctivitis, keratitis,and dacrocystitis related to infection by C. trachomatis, N.gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, orListeria spp.; disseminated Mycobacterium avium complex (MAC) diseaserelated to infection by Mycobacterium avium, or Mycobacteriumintracellulare; gastroenteritis related to infection by Campylobacterjejuni; intestinal protozoa related to infection by Cryptosporidium spp.odontogenic infection related to infection by viridans streptococci;persistent cough related to infection by Bordetella pertussis; gasgangrene related to infection by Clostridium perfringens or Bacteroidesspp.; Skin infection by S. aureus, Propionibacterium acne;atherosclerosis related to infection by Helicobacter pylori andChlamydia pneumoniae.
 19. The method according to claim 18 wherein theinfection is selected from the group consisting of pneumonia,otitis-media, sinusitus, bronchitis, tonsillitis, Propionibacterium acneand skin and soft tissue infection.
 20. The method according to claim 7wherein the infection or disorder is selected from the group consistingof bovine respiratory disease related to infection by P. haemolytica.,P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric diseaserelated to infection by E. coli or protozoa, dairy cow mastitis relatedto infection by S. aureus, S. uberis, S. agalactiae, S. dysgalactiae,Klebsiella spp., Corynebacterium, or Enterococcus spp.; swinerespiratory disease related to infection by A. pleuropneumoniae., P.multocida, or Mycoplasma spp.; swine enteric disease related toinfection by E. coli, Lawsonia intracellularis, Salmonella spp., orSerpulina hyodyisinteriae; cow footrot related to infection byFusobacterium spp.; cow metritis related to infection by E. coli; cowhairy warts related to Infection by Fusobacterium necrophorum orBacteroides nodosus; cow pink-eye related to infection by Moraxellabovis, cow premature abortion related to infection by protozoa; urinarytract infection in dogs and cats related to infection by E. coli; skinand soft tissue infections in dogs and cats related to infection by S.epidermidis, S. intermedius, coagulase neg. Staphylococcus or P.multocida; and dental or mouth infections in dogs and cats related toinfection by Alcaligenes spp., Bacteroides spp., Clostridium spp.,Enterobacter spp., Eubacterium spp., Peptostreptococcus spp.,Porphfyromonas spp., Campylobacter spp., Actinomyces spp.,Erysipelothrix spp., Rhodococcus spp., Trypanosoma spp., Plasmodiumspp., Babesia spp., Toxoplasma spp., Pneumocystis spp., Leishmania spp.,and Trichomonas spp, and Prevotella spp.
 21. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof the formula:

and pharmaceutically acceptable salts, esters, prodrugs, racemicmixtures and stereoisomers thereof, in combination with apharmaceutically acceptable carrier.
 22. A method for controlling abacterial infection in a subject, comprising administering to saidsubject a therapeutically effective amount of a pharmaceuticalcomposition according to claim 21.